α,β-unsaturated amide compound

ABSTRACT

An object of the present invention is to provide an α,β-unsaturated amide compound or a pharmaceutically acceptable salt or the like thereof having anticancer activity and the like. The α,β-unsaturated amide compound represented by the following formula (I) or a pharmaceutically acceptable salt or the like thereof has anticancer activity and the like:[wherein, “A” represents optionally substituted heterocyclic diyl,R1 represents hydrogen atom or optionally substituted lower alkyl,R2 represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group,X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy), —CH═CH—, −CO— or —NH—CO—, andn1 and n2 are the same or different, and each represents 0 or 1].

CROSS-REFERENCE TO RELATED APPLICATION

The present patent application claims priority to Japanese PatentApplication No. 2017-123231 filed on Jun. 23, 2017, the entiredisclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an α,β-unsaturated amide compound or apharmaceutically acceptable salt or the like thereof having anticanceractivity and the like.

BACKGROUND ART

Mesothelioma is the general term for tumors derived from mesothelialcells, wherein the sites of occurrence are mainly pleura, peritoneum andpericardium. Although there are malignant and benign types, malignantmesothelioma is associated with poor prognosis and a 5-year survivalrate of 10% or less. Therefore, the establishment of its treatmentmodality is strongly desired.

Most mesothelioma occurring in pleura and peritoneum is caused byexposure to asbestos, and it is known that the average incubation periodof mesothelioma is 40 years or more (Annals of Oncology, 2015, 26,1649-1660). Furthermore, mesothelioma is often treatment-resistant andhas low response to surgical remedy, radiotherapy or chemotherapy. Forchemotherapy, a combination therapy of cisplatin and pemetrexed is used(Journal of Clinical Oncology, 2003, 21, 2636-2644), but the meansurvival time is only approximately 12 months.

Lung cancer is defined as canceration of part of cells belonging totrachea, bronchi, or alveoli of lung for some reason. Early detection isdifficult, and the 5-year survival rate is 15% or less with poorprognosis (OncoTargets and Therapy, 2016, 9, 1023-1028). Theestablishment of a further treatment modality is desired.

Ovarian cancer occurs in ovaries which sit at both sides of the uterus,and there is a great variety of types of ovarian cancers such asepithelial, germ cell or sex cord-stromal tumor depending on the site ofoccurrence. However, 90% or more of ovarian cancer cases are epithelialtumors. The 5-year survival rate is 45% or less. It is reported thatthere are 15,000 fatal cases among ovarian cancers each year in theworld (Best Practice & Research Clinical Obstetrics and Gynaecology,2016, S1521-6934, 30091-30098). The establishment of a treatmentmodality is desired.

Liver cancer is classified roughly into two types: primary liver cancerand metastatic liver cancer that has metastasized from other organs.Primary liver cancer is classified as hepatoma and cholangioma. Mostprimary liver cancer is hepatoma. Primary liver cancer has apoor-prognosis, and it has been reported that the 5-year survival rateis 12 to 28% for hepatoma and, 25 to 40% for cholangioma (Journal ofGastrointestinal surgery, 2014, 18, 2136-2148). There are many cases ofrecurrence and the disease is resistant to systemic chemotherapy.Therefore, the establishment of a further treatment modality is desired.

As α,β-unsaturated amide compounds, known are, for example, anα,β-unsaturated amide compound having a phenyl group substituted with anaryloxy group as a melatonin receptor agonist (refer to patent document1), an α,β-unsaturated amide compound having a phenyl group substitutedwith an aryloxy group as a synthetic rubber component (refer to patentdocument 2), an α,β-unsaturated amide compound having a phenyl groupsubstituted with a heteroarylamino group as a protein kinase inhibitor(refer to patent document 3), an α,β-unsaturated amide compound having aphenyl group substituted with a heteroarylthio group as a Heat shockprotein 70 inhibitor (refer to patent document 4), an α,β-unsaturatedamide compound having a pyridyl group substituted with an aryloxy groupas a sodium-potassium exchanger inhibitor (refer to non-patent document1), an α,β-unsaturated amide compound having a quinolyl groupsubstituted with an anilino group as an epidermal growth factor receptorinhibitor (refer to patent document 5), an α,β-unsaturated amidecompound having a 3-cyanoquinolyl group as a tyrosine kinase inhibitor(refer to patent document 6), an α,β-unsaturated amide compound havingan aminopyrimidyl group as an epidermal growth factor receptor inhibitor(refer to patent document 7), an α,β-unsaturated amide compound having abenzimidazolyl group as an ion channel modulator (refer to patentdocument 8), and an α,β-unsaturated amide compound having a2,3-dihydrobenzo furyl group as a therapeutic drug for hepatic disease(refer to patent document 9) and the like.

PRIOR ART DOCUMENTS Patent Documents

-   [Patent Document 1] WO 1999/048859-   [Patent Document 2] EP 409565(A1)-   [Patent Document 3] WO 2009/051822-   [Patent Document 4] WO 2011/022440-   [Patent Document 5] WO 2004/032909-   [Patent Document 6] U.S. Pat. No. 6,002,008-   [Patent Document 7] WO 2015/188777-   [Patent Document 8] WO 2005/042497-   [Patent Document 9] WO 1998/09956

Non-Patent Documents

-   [Non-patent Document 1] Bioorganic & Medicinal Chemistry, 2004, Vol.    12, p. 5039-5056.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an α,β-unsaturatedamide compound or a pharmaceutically acceptable salt or the like thereofhaving anticancer activity and the like.

The present invention relates to the following clauses (1) to (36).

-   (1) An α,β-unsaturated amide compound represented by the following    formula (I) or a pharmaceutically acceptable salt thereof:

[wherein,

“A” represents optionally substituted heterocyclic diyl,

R¹ represents hydrogen atom or optionally substituted lower alkyl,

R² represents optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted aliphatic heterocyclic group oroptionally substituted aromatic heterocyclic group,

X represents —O—, —S—, —SO₂—, —NR^(X1)— (wherein, R^(X1) representshydrogen atom or lower alkyl), —CHR^(X2)— (wherein, R^(X2) representshydrogen atom or hydroxy), —CH═CH—, —CO— or —NH—CO—, and

n1 and n2 are the same or different, and each represents 0 or 1].

-   (2) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is heterocyclic diyl selected from the group    consisting of benzoxazolediyl, benzothiazolediyl,    2,3-dihydrobenzothiophenediyl, 3,4-dihydropyranopyridinediyl,    2,3,4,5-tetrahydrobenzoxazepinediyl,    2,3,4,5-tetrahydrobenzoxepinediyl and 2,3-dihydrobenzofurandiyl.-   (3) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is benzoxazolediyl.-   (4) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (3), wherein the    benzoxazolediyl is benzoxazolediyl selected from the group    consisting of the following formulae (A1-1), (A1-2), (A1-3) and    (A1-4):

{wherein, —[X] represents bonding position of the group represented informula (A-1):

(wherein, X, R² and n2 are each the same as the definition described inclause (1))

-[ACP] represents bonding position of the group represented in formula(A-2):

(wherein, R¹ and n1 are each the same as the definition described inclause (1))}.

-   (5) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is benzothiazolediyl.-   (6) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (5), wherein the    benzothiazolediyl is benzothiazolediyl represented by the following    formula (A2-1) or (A2-2):

(wherein, —[X] and -[ACP] are each the same as the definition describedin clause (4)).

-   (7) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is 2,3-dihydrobenzothiophenediyl.-   (8) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (7), wherein the    2,3-dihydrobenzothiophenediyl is 2,3-dihydrobenzothiophenediyl    represented by the following formula (A4-1):

(wherein, —[X] and -[ACP] are each the same as the definitions describedin clause (4)).

-   (9) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is 3,4-dihydropyranopyridinediyl.-   (10) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (9), wherein the    3,4-dihydropyranopyridinediyl is 3,4-dihydropyranopyridinediyl    represented by the following formula (A5-1):

(wherein, —[X] and -[ACP] are each the same as the definition describedin clause (4)).

-   (11) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is 2,3,4,5-tetrahydrobenzoxazepinediyl.-   (12) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (11), wherein the    2,3,4,5-tetrahydrobenzoxazepinediyl is    2,3,4,5-tetrahydrobenzoxazepinediyl represented by the following    formula (A6-1):

(wherein, —[X] and -[ACP] are each the same as the definition describedin clause (4)).

-   (13) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is 2,3,4,5-tetrahydrobenzoxepinediyl.-   (14) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (13), wherein the    2,3,4,5-tetrahydrobenzoxepinediyl is    2,3,4,5-tetrahydrobenzoxepinediyl represented by the following    formula (A7-1):

(wherein, —[X] and -[ACP] are each the same as the definition describedin clause (4)).

-   (15) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (1), wherein the    heterocyclic diyl is 2,3-dihydrobenzofurandiyl.-   (16) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (15), wherein the    2,3-dihydrobenzofurandiyl is 2,3-dihydrobenzofurandiyl selected from    the group consisting of the following formulae (A8-1), (A8-2) and    (A8-3):

(wherein, —[X] and -[ACP] are each the same as the definition describedin clause (4)).

-   (17) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (16),    wherein R¹ is hydrogen atom.-   (18) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (17),    wherein R² is optionally substituted aryl or optionally substituted    aromatic heterocyclic group.-   (19) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (18),    wherein n2 is 0.-   (20) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (19),    wherein X is —O—.-   (21) A pharmaceutical composition comprising the α,β-unsaturated    amide compound or a pharmaceutically acceptable salt thereof    according to any one of clauses (1) to (20) and a carrier.-   (22) The pharmaceutical composition according to clause (21) for the    treatment or prevention of cancer.-   (23) The pharmaceutical composition according to clause (22),    wherein the cancer is one or two or more selected from the group    consisting of mesothelioma, lung cancer, ovarian cancer, and liver    cancer.-   (24) A method for the treatment or prevention comprising    administration of the α,β-unsaturated amide compound or a    pharmaceutically acceptable salt thereof according to any one of    clauses (1) to (20) to a subject.-   (25) The method for the treatment or prevention according to clause    (24), wherein the method is a method for the treatment or prevention    of cancer.-   (26) The method for the treatment or prevention according to clause    (25), wherein the cancer is one or two or more selected from the    group consisting of mesothelioma, lung cancer, ovarian cancer, and    liver cancer.-   (27) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (20)    for use as a medicine.-   (28) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (20)    for use in the treatment or prevention of cancer.-   (29) The α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to clause (28), wherein the cancer    is one or two or more selected from the group consisting of    mesothelioma, lung cancer, ovarian cancer, and liver cancer.-   (30) Use of the α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (20)    for the manufacture of a medicine for treating or preventing cancer.-   (31) The use according to clause (30), wherein the cancer is one or    two or more selected from the group consisting of mesothelioma, lung    cancer, ovarian cancer, and liver cancer.-   (32) Use of the α,β-unsaturated amide compound or a pharmaceutically    acceptable salt thereof according to any one of clauses (1) to (20)    for treating or preventing cancer.-   (33) The use according to clause (32), wherein the cancer is one or    two or more selected from the group consisting of mesothelioma, lung    cancer, ovarian cancer, and liver cancer.-   (34) A medicine comprising the α,β-unsaturated amide compound or a    pharmaceutically acceptable salt thereof according to any one of    clauses (1) to (20) as an active ingredient.-   (35) A prophylactic or therapeutic agent for cancer comprising the    α,β-unsaturated amide compound or a pharmaceutically acceptable salt    thereof according to any one of clauses (1) to (20) as an active    ingredient.-   (36) The prophylactic or therapeutic agent according to clause (35),    wherein the cancer is one or two or more selected from the group    consisting of mesothelioma, lung cancer, ovarian cancer, and liver    cancer.

The present invention provides an α,β-unsaturated amide compound or apharmaceutically acceptable salt thereof or the like thereof havinganticancer activity and the like.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, an α,β-unsaturated amide compoundrepresented by the following formula (I) or a pharmaceuticallyacceptable salt thereof is provided:

[wherein,

“A” represents optionally substituted heterocyclic diyl,

R¹ represents hydrogen atom or optionally substituted lower alkyl,

R² represents optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted aliphatic heterocyclic group oroptionally substituted aromatic heterocyclic group,

X represents —O—, —S—, —SO₂—, —NR^(X1)— (wherein, R^(X1) representshydrogen atom or lower alkyl), —CHR^(X2)— (wherein, R^(X2) representshydrogen atom or hydroxy), —CH═CH—, —CO— or —NH—CO—, and

n1 and n2 are the same or different, and each represents 0 or 1].

A compound represented by general formula (I) is hereinafter referred toas compound (I). The same applies to a compound of other formula number.

In the above general formula (I), “A” represents optionally substitutedheterocyclic diyl.

A heterocyclic diyl group includes, for example, a group formed byremoving one hydrogen atom from the group exemplified in the aliphaticheterocyclic group and the aromatic heterocyclic group in R² mentionedbelow, and more specifically aziridinediyl, azetidinediyl,pyrrolidinediyl, piperidinediyl, azepanediyl,1,2,5,6-tetrahydropyridinediyl, imidazolidinediyl, pyrazolidinediyl,piperazinediyl, homopiperazinediyl, pyrazolinediyl, oxiranediyl,tetrahydrofurandiyl, tetrahydro-2H-pyrandiyl, 5,6-dihydro-2H-pyrandiyl,oxazolidinediyl, morpholinediyl, thioxazolidinediyl, thiomorpholinediyl,2H-oxazolediyl, 2H-thioxazolediyl, dihydroindolediyl,dihydroisoindolediyl, dihydrobenzofurandiyl, benzimidazolinediyl,dihydrobenzoxazolediyl, dihydrobenzothioxazolediyl, benzodioxolediyl,1,2,3,4-tetrahydroquinolinediyl, 5,6,7,8-tetrahydroquinolinediyl,1,2,3,4-tetrahydroisoquinolinediyl, chromanediyl, isochromanediyl,coumarinediyl, isocoumarinediyl, 1,2,3,4-tetrahydroquinoxalinediyl,5,6,7,8-tetrahydroquinoxalinediyl, 5,6,7,8-tetrahydroquinazolinediyl,benzodioxanediyl, furandiyl, thiophenediyl, pyrrolediyl, imidazolediyl,pyrazolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, thiazolediyl,isothiazolediyl, thiadiazolediyl, triazolediyl, tetrazolediyl,pyridinediyl, pyridazinediyl, pyrimidinediyl, pyrazinediyl,triazinediyl, benzofurandiyl, benzothiophenediyl, benzoxazolediyl,benzothiazolediyl, isoindoledlyl, indolediyl, indazoledlyl,benzimidazolediyl, benzotriazolediyl, oxazolopyrimidinediyl,thiazolopyrimidinediyl, pyrrolopyridinediyl, pyrrolopyrimidinediylimidazopyridinediyl purinediyl quinolinediyl isoquinolinediylcinnolinediyl phthalazinediyl quinazolinediyl, quinoxalinediyl,naphthyridinediyl, and the like. The one hydrogen atom removed may beany hydrogen atom on the aliphatic heterocyclic group or the aromaticheterocyclic group.

According to a preferred embodiment of the present invention, theheterocyclic diyl is heterocyclic diyl selected from the groupconsisting of benzoxazolediyl, benzothiazolediyl,2,3-dihydrobenzothiophenediyl, 3,4-dihydropyranopyridinediyl,2,3,4,5-tetrahydrobenzoxazepinediyl, 2,3,4,5-tetrahydrobenzoxepinediyland 2,3-dihydrobenzofurandiyl.

According to a preferred embodiment of the present invention, theheterocyclic diyl is benzoxazolediyl.

According to a preferred embodiment of the present invention, thebenzoxazolediyl is benzoxazolediyl selected from the group consisting ofthe following formulae (A1-1), (A1-2), (A1-3), and (A1-4):

{wherein, —[X] represents bonding position of the group represented informula (A-1):

(wherein, X, R² and n2 are each the same as the definition describedabove)

-[ACP] represents bonding position of the group represented in formula(A-2):

(wherein, R¹ and n1 are each the same as the definition describedabove)}.

According to a preferred embodiment of the present invention, theheterocyclic diyl is benzothiazolediyl.

According to a preferred embodiment of the present invention, thebenzothiazolediyl is benzothiazolediyl represented by the followingformula (A2-1) or (A2-2):

(wherein, —[X] and -[ACP] are each the same as the definition describedabove).

According to a preferred embodiment of the present invention, theheterocyclic diyl is 2,3-dihydrobenzothiophenediyl.

According to a preferred embodiment of the present invention, the2,3-dihydrobenzothiophenediyl is 2,3-dihydrobenzothiophenediylrepresented by the following formula (A4-1):

(wherein, —[X] and -[ACP] are each the same as the definitions describedabove).

According to a preferred embodiment of the present invention, theheterocyclic diyl is 3,4-dihydropyranopyridinediyl.

According to a preferred embodiment of the present invention, the3,4-dihydropyranopyridinediyl is 3,4-dihydropyranopyridinediylrepresented by the following formula (A5-1):

(wherein, —[X] and -[ACP] are each the same as the definition describedabove).

According to a preferred embodiment of the present invention, theheterocyclic diyl is 2,3,4,5-tetrahydrobenzoxazepinediyl.

According to a preferred embodiment of the present invention, the2,3,4,5-tetrahydrobenzoxazepinediyl is2,3,4,5-tetrahydrobenzoxazepinediyl represented by the following formula(A6-1):

(wherein, —[X] and -[ACP] are each the same as the definition describedabove).

According to a preferred embodiment of the present invention, theheterocyclic diyl is 2,3,4,5-tetrahydrobenzoxepinediyl.

According to a preferred embodiment of the present invention, the2,3,4,5-tetrahydrobenzoxepinediyl is 2,3,4,5-tetrahydrobenzoxepinediylrepresented by the following formula (A7-1):

(wherein, —[X] and -[ACP] are each the same as the definition describedabove).

According to a preferred embodiment of the present invention, theheterocyclic diyl is 2,3-dihydrobenzofurandiyl.

According to a preferred embodiment of the present invention, the2,3-dihydrobenzofurandiyl is 2,3-dihydrobenzofurandiyl selected from thegroup consisting of the following formulae (A8-1), (A8-2) and (A8-3):

(wherein, —[X] and -[ACP] are each the same as the definition describedabove).

In general formula (I) mentioned above, R¹ represents hydrogen atom oroptionally substituted lower alkyl, and is preferably hydrogen atom.

Lower alkyl in the present description includes, for example, straightor branched chain alkyl having 1-10 carbon atoms and more specificallyincludes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl and the like.

In general formula (I) mentioned above, R² represents optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted aliphatic heterocyclic group or optionally substitutedaromatic heterocyclic group, and preferably optionally substituted arylor optionally substituted aromatic heterocyclic group.

Aryl in the present description includes, for example, aryl having 6-14carbon atoms, and more specifically includes phenyl, naphthyl, azulenyl,and anthryl and the like.

Aryl in R² is preferably phenyl.

Cycloalkyl in the present description includes, for example, cycloalkylhaving 3-10 carbon atoms, and more specifically includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, and cyclodecanyl and the like.

Aliphatic heterocyclic group in the present description includes, forexample, 5- or 6-membered monocyclic aliphatic heterocyclic groupcontaining at least one atom selected from nitrogen atom, oxygen atom,and sulfur atom, and ring-fused aliphatic heterocyclic group and thelike formed by fusing 3- to 8-membered rings in a bicyclic or tricyclicring and containing at least one atom selected from nitrogen atom,oxygen atom, and sulfur atom; and more specifically includes aziridinyl,azetidinyl, pyrrolidinyl, piperidine, piperidinyl, azepanyl,1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl,homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl,tetrahydro-2H-pyranyl, dioxanyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl,morpholine, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl,2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl,benzimidazolinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl,benzodioxolyl, 1,2,3,4-tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl,1,2,3,4-tetrahydroisoquinolyl, chromanyl, isochromanyl, 2H-chromenyl,4H-chromenyl, 1,2,3,4-tetrahydroquinoxalinyl,5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolinyl, andbenzodioxanyl and the like.

Aromatic heterocyclic group in the present description includes, forexample, 5- or 6-membered monocyclic aromatic heterocyclic groupcontaining at least one atom selected from nitrogen atom, oxygen atom,and sulfur atom, and ring-fused aromatic heterocyclic group and the likeformed by fusing 3- to 8-membered rings in a bicyclic or tricyclic ringand containing at least one atom selected from nitrogen atom, oxygenatom and sulfur atom, and more specifically includes furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl,indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl,thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.

Substituents in the optionally substituted lower alkyl are the same ordifferent, and each include, for example, with the number ofsubstitution of 1-3, a substituent selected from the group consisting ofhalogen, hydroxy, mercapto, nitro, cyano, carboxy, carbamoyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, aliphatic heterocyclic group, aromaticheterocyclic group, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkoxy, C₆₋₁₄ aryloxy,C₇₋₁₆ aralkyloxy, C₂₋₁₁ alkanoyloxy, C₇₋₁₅ aroyloxy, C₁₋₁₀ alkylthio,—NR^(X)R^(Y) (wherein, R^(X) and R^(Y) are the same or different andeach represent hydrogen atom, C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,aromatic heterocyclic group, C₇₋₁₆ aralkyl, C₂₋₁₁ alkanoyl, C₇₋₁₅ aroyl,C₁₋₁₀ alkoxycarbonyl or C₇₋₁₆ aralkyloxycarbonyl), C₂₋₁₁ alkanoyl, C₇₋₁₅aroyl, C₁₋₁₀ alkoxycarbonyl, C₆₋₁₄ aryloxycarbonyl, C₁₋₁₀alkylcarbamoyl, and di-C₁₋₁₀ alkylcarbamoyl.

Substituents in the optionally substituted aryl and the optionallysubstituted aromatic heterocyclic group are the same or different, andeach include, for example, with the number of substitution of 1-3, asubstituent selected from the group consisting of halogen, hydroxy,mercapto, nitro, cyano, carboxy, carbamoyl, optionally substituted C₁₋₁₀alkyl (substituents in the optionally substituted C₁₋₁₀ alkyl are thesame or different, and each include, for example, halogen with thenumber of substitution of 1-3 and the like), C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, p-toluenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyl, trifluoromethanesulfonyloxy, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, aliphatic heterocyclic group, aromatic heterocyclic group,optionally substituted C₁₋₁₀ alkoxy (substituents in the optionallysubstituted C₁₋₁₀ alkoxy are the same or different, and each include,for example, halogen with the number of substitution of 1-3 and thelike), C₃₋₁₀ cycloalkoxy, C₆₋₁₄ aryloxy, C₇₋₁₆ aralkyloxy, C₂₋₁₁alkanoyloxy, C₇₋₁₅ aroyloxy, C₁₋₁₀ alkylthio optionally substituted(substituents in the C₁₋₁₀ alkylthio optionally substituted are the sameor different, and each include, for example, halogen with the number ofsubstitution of 1-3), —NR^(Xa)R^(Ya) (wherein, R^(Xa) and R^(Ya) are thesame or different, and each represent hydrogen atom, C₁₋₁₀ alkyl,cycloalkyl, C₆₋₁₄ aryl, aromatic heterocyclic group, C₇₋₁₆ aralkyl,C₂₋₁₁ alkanoyl, C₇₋₁₅ aroyl, C₁₋₁₀ alkoxycarbonyl or C₇₋₁₆aralkyloxycarbonyl), C₂₋₁₁ alkanoyl, C₇₋₁₅ aroyl, alkoxycarbonyl, C₆₋₁₄aryloxycarbonyl, C₁₋₁₀ alkylcarbamoyl, and di-C₁₋₁₀ alkylcarbamoyl.

Substituents in the optionally substituted cycloalkyl and the optionallysubstituted aliphatic heterocyclic group are the same or different, andeach include, for example, with the number of substitution of 1-3, asubstituent selected from the group consisting of oxo, halogen(preferably fluorine atom), hydroxy, mercapto, nitro, cyano, carboxy,carbamoyl, C₁₋₁₀ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, optionally substituted aliphaticheterocyclic group (substituents in the optionally substituted aliphaticheterocyclic group are the same or different, and include, for example,halogen with the number of substitution of 1-3 and the like), aromaticheterocyclic group, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkoxy, C₆₋₁₄ aryloxy,C₇₋₁₆ aralkyloxy, C₂₋₁₁ alkanoyloxy, C₇₋₁₅ aroyloxy, C₁₋₁₀ alkylthio,—NR^(Xb)R^(Yb) (wherein, R^(Xb) and R^(Yb) are the same or different,and each represent hydrogen atom, C₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, aromatic heterocyclic group, C₇₋₁₆ aralkyl, C₂₋₁₁ alkanoyl, C₇₋₁₅aroyl, C₁₋₁₀ alkoxycarbonyl or C₇₋₁₆ aralkyloxycarbonyl), C₂₋₁₁alkanoyl, C₇₋₁₅ aroyl, C₁₋₁₀ alkoxycarbonyl, C₆₋₁₄ aryloxy carbonyl,C₁₋₁₀ alkylcarbamoyl and di-C₁₋₁₀ alkylcarbamoyl.

Substituents in the optionally substituted heterocyclic diyl are thesame or different, and each include, for example, with the number ofsubstitution of 1-3, a substituent selected from the group consisting ofhalogen (preferably chlorine atom, fluorine atom or bromine atom),hydroxy, mercapto, nitro, cyano, carboxy, carbamoyl, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, trifluoromethyl, p-toluenesulfonyloxy,methanesulfonyloxy, trifluoromethanesulfonyloxy, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, optionally substituted aliphatic heterocyclic group (substituentsin the optionally substituted aliphatic heterocyclic group are the sameor different, and each include, for example, halogen with the number ofsubstitution of 1-3 and the like), aromatic heterocyclic group,optionally substituted C₁₋₁₀ alkoxy (substituents in the optionallysubstituted C₁₋₁₀ alkoxy are the same or different, and each include,for example, halogen with the number of substitution of 1-3 and thelike), C₃₋₁₀ cycloalkoxy, C₆₋₁₄ aryloxy, C₇₋₁₆ aralkyloxy, C₂₋₁₁alkanoyloxy, C₇₋₁₅ aroyloxy, C₁₋₁₀ alkylthio, —NR^(Xc)R^(Yc) (wherein,R^(Xc) and R^(Yc) are the same or different, and each represent hydrogenatom, optionally substituted C₁₋₁₀ alkyl (substituents in the optionallysubstituted C₁₋₁₀ alkyl are the same or different, and each include forexample, with the number of substitution of 1-3, C₁₋₁₀ alkylamino, anddi-C₁₋₁₀ alkylamino and the like), C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,aromatic heterocyclic group, C₇₋₁₆ aralkyl, C₂₋₁₁ alkanoyl, C₇₋₁₅ aroyl,C₁₋₁₀ alkoxycarbonyl or C₇₋₁₆ aralkyloxycarbonyl), C₂₋₁₁ alkanoyl, C₇₋₁₅aroyl, C₁₋₁₀ alkoxycarbonyl, C₆₋₁₄ aryloxy carbonyl, C₁₋₁₀alkylcarbamoyl, and di-C₁₋₁₀ alkylcarbamoyl.

In general formula (I) mentioned above, X represents —O—, —S—, —SO₂—,—NR^(X1)— (wherein, R^(X1) represents hydrogen atom or lower alkyl),—CHR^(X2)— (wherein, R^(X2) represents hydrogen atom or hydroxy),—CH═CH—, —CO— or —NH—CO—, preferably —O—, —S—, —N^(X1)— (wherein, R^(X1)represents hydrogen atom or lower alkyl), —CHR^(X2)— (wherein, R^(X2)represents hydrogen atom), —CH═CH— or —CO. According to a preferredembodiment of the present invention, X is —O—.

In general formula (I) mentioned above, n1 and n2 are the same ordifferent, and each represent 0 or 1. According to a preferredembodiment of the present invention, n2 is 0.

When substituents in the optionally substituted heterocyclic diyl arebonded to an sp³ carbon constituting the heterocyclic diyl, the abovesubstituent may be, for example, substituted with oxo with the number ofsubstitution of 1-3. Here, the sp³ carbon refers to a carbon atomforming an sp³ hybrid orbit. In the present description, a sp² carbonalso similarly refers to a carbon atom forming sp² hybrid orbit.

Alkyl moieties of C₁₋₃ alkyl and C₁₋₁₀ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxy,C₂₋₁₁ alkanoyloxy, C₁₋₃ alkylthio, C₁₋₁₀ alkylthio, C₂₋₁₁ alkanoyl,C₁₋₁₀ alkoxycarbonyl, C₁₋₁₀ alkylamino, di-C₁₋₃ alkylamino, di-C₁₋₁₀alkylamino, C₁₋₁₀ alkylcarbamoyl, and di-C₁₋₁₀ alkylcarbamoyl, as shownhere, are exemplified, for example, by the groups given in the abovelower alkyl examples. Two alkyl moieties in di-C₁₋₃ alkylamino, di-C₁₋₁₀alkylamino, and di-C₁₋₁₀ alkylcarbamoyl may be the same or different.

C₃₋₅ cycloalkyl and C₃₋₁₀ cycloalkyl and cycloalkyl moieties of C₃₋₁₀cycloalkoxy are exemplified, for example, by the groups given in theabove cycloalkyl examples.

C₆₋₁₄ aryl and aryl moieties of C₆₋₁₄ aryloxy, C₇₋₁₅ aroyl, C₇₋₁₅aroyloxy and C₆₋₁₄ aryloxycarbonyl are exemplified by the groups givenin the above aryl examples.

Aryl moieties of C₇₋₉ aralkyloxy, C₇₋₁₆ aralkyloxy, C₇₋₁₆ aralkyl, andC₇₋₁₆ aralkyloxycarbonyl are exemplified by the groups given in theabove aryl examples. Alkyl moiety thereof include, for example, C₁₋₁₀alkylene, and more specifically a group formed by removing one hydrogenatom from the groups given in the above lower alkyl examples.

C₂₋₁₀ alkenyl represents, for example, straight or branched chainalkenyl having 2-10 carbon atoms, and more specifically includes vinyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, anddecenyl and the like.

In the present description, C₂₋₁₀ alkynyl represents, for example,straight or branched chain alkynyl having 2-10 carbon atoms, and morespecifically includes ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, and decynyl and the like.

In the present description, aliphatic heterocyclic group and aromaticheterocyclic group are the same as defined above, respectively.

In the present description, halogen means fluorine, chlorine, bromine oriodine atom.

According to a preferred embodiment of the compound (compound (I))represented by general formula (I), in the above formula (I),

“A” represents optionally substituted heterocyclic diyl, wherein theheterocyclic diyl is heterocyclic diyl selected from the groupconsisting of benzoxazolediyl, benzothiazolediyl, and2,3-dihydrobenzofurandiyl,

the heterocyclic diyl is optionally substituted with the number ofsubstitution of 1 or 2 (preferably the number of substitution of 1),with halogen (preferably chlorine atom, fluorine atom or bromine atom),trifluoromethyl, C₁₋₃ alkyl, or phenyl,

R¹ represents hydrogen atom or optionally substituted C₁₋₃ alkyl(preferably hydrogen atom or trifluoromethyl),

R² represents optionally substituted aryl (preferably phenyl),optionally substituted aromatic heterocyclic group (preferably pyridyl),or C₃-C₁₀ cycloalkyl (preferably cyclohexyl),

wherein,

the aryl in R² is optionally substituted with the number of substitutionof 1 or 2, with halogen (preferably chlorine atom or fluorine atom),cyano, trifluoromethyl, C₁₋₅ alkoxy (preferably methoxy), or—NR^(Xa)R^(Ya) (wherein, R^(Xa) and R^(Ya) are the same or different andrepresent C₁₋₃ alkyl) (preferably dimethylamine),

the aromatic heterocyclic group in R² is optionally substituted with thenumber of substitution of 1, with trifluoromethyl,

X represents —O—, —S—, —SO₂—, —NR^(X1)— (wherein, R^(X1) representshydrogen atom or C₁₋₃ alkyl), —CHR^(X2)— (wherein, R^(X2) representshydrogen atom or hydroxy), —CH═CH— or —NH—CO—, and

n1 and n2 are the same or different and each represent 0 or 1.

According to a more preferred embodiment of the compound (compound (I))represented by general formula (I), in the above formula (I),

“A” represents optionally substituted benzoxazolediyl, the heterocyclicdiyl is optionally substituted with the number of substitution of 1 or 2(preferably the number of substitution of 1), with trifluoromethyl, C₁₋₃alkyl, or phenyl,

R¹ represents hydrogen atom or optionally substituted C₁₋₃ alkyl(preferably hydrogen atom),

R² represents optionally substituted aryl (preferably phenyl),optionally substituted aromatic heterocyclic group (preferably pyridyl),or C₃-C₁₀ cycloalkyl (preferably cyclohexyl),

wherein,

the aryl in R² is optionally substituted with the number of substitutionof 1 or 2, with halogen (preferably chlorine atom or fluorine atom),cyano, trifluoromethyl, C₁₋₅ alkoxy (preferably methoxy), or—NR^(Xa)R^(Ya) (wherein, R^(Xa) and R^(Ya) are the same or different andrepresent C₁₋₃ alkyl) (preferably dimethylamine),

the aromatic heterocyclic group in R² is optionally substituted with thenumber of substitution of 1, with trifluoromethyl,

X represents —O—, —S—, —SO₂—, —NR^(X1)— (wherein, R^(X1) representshydrogen atom or lower alkyl), —CHR^(X2)— (wherein, R^(X2) representshydrogen atom or hydroxy), —CH═CH— or —NH—CO—, and

n1 and n2 are the same or different and each represent 0 or 1.

According to a further preferred embodiment of the compound (compound(I)) represented by general formula (I), in the above formula (I),

“A” represents optionally substituted benzoxazolediyl, the heterocyclicdiyl is optionally substituted with the number of substitution of 1,with trifluoromethyl, C₁₋₃ alkyl, or phenyl,

R¹ represents hydrogen atom,

R² represents optionally substituted phenyl, or optionally substitutedpyridyl,

wherein,

the phenyl in R² is optionally substituted with the number ofsubstitution of 1 or 2, with halogen (preferably chlorine atom orfluorine atom), cyano, trifluoromethyl, C₁₋₅ alkoxy (preferablymethoxy), or —NR^(Xa)R^(Ya) (wherein, R^(Xa) and R^(Ya) are the same ordifferent and represent C₁₋₃ alkyl) (preferably dimethylamine),

the pyridyl in R² is optionally substituted with the number ofsubstitution of 1, with trifluoromethyl,

X represents —O—, —S—, —SO₂—, —NR^(X1)— (wherein, R^(X1) representshydrogen atom or lower alkyl), —CHR^(X2)— (wherein, R^(X2) representshydrogen atom or hydroxy) or —CH═CH— (preferably X represents —O—, —S—,(wherein, R^(X1) represents hydrogen atom or lower alkyl), or —CHR^(X2)—(wherein, R^(X2) represents hydroxy)), and

n1 and n2 are the same or different and each represent 0 or 1.

According to another more preferred embodiment of the compound (compound(I)) represented by general formula (I), in the above formula (I),

“A” represents optionally substituted benzothiazolediyl,

the heterocyclic diyl is optionally substituted with the number ofsubstitution of 1 or 2 (preferably the number of substitution of 1),with C₁₋₃ alkyl,

R¹ represents hydrogen atom,

R² represents optionally substituted aryl (preferably phenyl), oroptionally substituted aromatic heterocyclic group (preferably pyridyl),

wherein,

the aryl in R² is optionally substituted with the number of substitutionof 1, with trifluoromethyl,

the aromatic heterocyclic group in R² is optionally substituted with thenumber of substitution of 1, with trifluoromethyl,

X represents —O—, and

n1 represents 1 and n2 represents 0.

According to another more preferred embodiment of the compound (compound(I)) represented by general formula (I), in the above formula (I),

“A” represents optionally substituted 2,3-dihydrobenzofurandiyl (here,2,3-dihydrobenzofurandiyl is preferably represented by above formula(A8-1)),

the heterocyclic diyl is optionally substituted with the number ofsubstitution of 1 or 2 (preferably the number of substitution of 1),with halogen (preferably bromine atom) or C₁₋₃ alkyl,

R¹ represents hydrogen atom,

R² represents optionally substituted aryl (preferably phenyl),

wherein,

the aryl in R² is optionally substituted with the number of substitutionof 1, with trifluoromethyl,

X represents —O—, and

n1 represents 0 and n2 represents 0.

The pharmaceutically acceptable salt of compound (I) includes, forexample, pharmaceutically acceptable acid addition salt, metal salt,ammonium salt, organic amine addition salt, and amino acid addition saltand the like. Pharmaceutically acceptable acid addition salt of compound(I) includes, for example, inorganic acid salt such as hydrochloride,hydrobromide, nitrate, sulfate, and phosphate and the like, and organicacid salt such as acetate, oxalate, maleate, fumarate, citrate,benzoate, and methanesulfonate and the like; pharmaceutically acceptablemetal salt includes, for example, alkali metal salt such as sodium saltand potassium salt and the like, and alkali earth metal salt such asmagnesium salt, and calcium salt and the like, aluminum salt, and zincsalt and the like; pharmaceutically acceptable ammonium salt include,for example, salt of such as ammonium and tetramethylammonium and thelike; pharmaceutically acceptable organic amine addition salt includes,for example, addition salt of such as morpholine and piperidine and thelike; pharmaceutically acceptable amino acid addition salt includes, forexample, addition salt of such as lysine, glycine, phenylalanine,aspartic acid, and glutaminic acid and the like.

The wavy line between R¹ and the carbon atom adjacent to R¹ in compound(I) indicates a cis- or trans-configuration.

The compound of the present invention involves a compound havingpreferred properties on one or more evaluation items required for apharmaceutical composition, or a prophylactic or therapeutic agent forcancer such as pharmacological activity, physical stability, stabilityunder physiological conditions, safety for living body, and the like.

Manufacturing Method of Compound (I)

Next, manufacturing methods of compound (I) will be explained.

For the manufacturing method described below, when the defined groupsare altered under the conditions of the manufacturing method or themethod is not appropriate to conduct, target compounds can bemanufactured by using a method of introducing or removing a protectinggroup commonly used in synthetic organic chemistry [e.g., a methoddescribed in Protective Groups in Organic Synthesis, third edition by T.W. Greene, John Wiley & Sons Inc. (1999), and the like] and the like.Furthermore, the order of the reaction steps such as the introduction ofsubstituents and the like can be changed as needed.

The compounds (I) can be manufactured according to the following steps.

Manufacturing Method 1

In manufacturing method 10, among compounds (II) that are precursors ofcompounds (I), compounds (II-a), (II-b) and (II-c) as 4-aminochromanederivatives and compound (II-d) as a 4-aminomethylchromane derivativecan be manufactured according to the following steps:

(wherein R² and n2 are the same as the definition described above;R^(2A) represents optionally substituted aryl or optionally substitutedaromatic heterocyclic group in R²; R³ represents lower alkyl; R⁴represents lower alkyl, fluorine atom, chlorine atom, bromine atom oriodine atom; R⁵ represents the substituent mentioned above as thesubstituent of optionally substituted heterocyclic diyl or hydrogenatom; E¹ represents CR^(a)R^(b) (wherein R^(a) and R^(b) are the same ordifferent, and each represents the substituent mentioned above as thesubstituent of optionally substituted heterocyclic diyl or hydrogenatom); X¹ and X² are the same or different, and each represents aleaving group such as chlorine atom, bromine atom, iodine atom,p-toluenesulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxyor the like; and M¹ represents MgI, MgBr, MgCl, Li, and the like).Step 1

Compound (III-b) can be manufactured by reacting compound (III-a) in asolvent with an ammonia source preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours in the presence of a reducing agent preferablyin 1 to 10 equivalent amount, an acid preferably in 1 to 10 equivalentamount, and if needed, a metallic catalyst preferably in 0.01 to 1equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

Compound (III-a) can be obtained as a commercially available product, orby well-known methods (e.g., WO2015/051447, WO2001/18006, WO1998/13356,Bioorganic & Medicinal Chemistry, 2007, 17, 1288-1290, and the like) ortheir equivalent methods.

The ammonia sources include, for example, ammoniacal water, ammoniumformate, and ammonium acetate and the like.

The reducing agents include, for example, sodium triacetoxyborohydride,and sodium cyanoborohydride and the like.

The acids include, for example, hydrochloric acid, sulfuric acid, formicacid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid andthe like.

The metallic catalysts include, for example,dichloro(pentamethylcyclopentadienyl)rhodium(III), andchloro[N-{4-(dimethylamino)phenyl}-2-pyridinecarboxyamidate](pentamethylcyclopentadienyl)iridium(III) and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME),1,4-dioxane, N,N-dimethylformamide (DMF), N,N-dimethyl acetamide (DMA),N-methyl-2-pyrrolidone (NMP), and water and the like. They are usedalone or in mixtures.

Step 2

Compound (II-a), wherein n2 is 0 and R² is optionally substituted arylor optionally substituted aromatic heterocyclic group, can bemanufactured by reacting compound (III-b) in a solvent with compound(a-3) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hoursin the presence of a copper reagent in preferably 0.01 to 1 equivalentamount, a ligand in preferably 0.01 to 1 equivalent amount, and a basein preferably 1 to 10 equivalent amount, at a temperature between −20°C. and the boiling point of the solvent used.

Compound (a-3) can be obtained as a commercially available product.

The copper reagents include, for example, copper(0), copper(I) iodide,copper(II) acetate, copper(II) oxide, and copper(I) chloride and thelike.

The ligands include, for example, phenanthroline,trans-1,2-cyclohexanediamine, and picolinic acid and the like.

The bases include, for example, potassium carbonate, cesium carbonate,lithium chloride, potassium chloride, potassium tert-butoxide, sodiumtert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodiumcarbonate, sodium hydroxide, potassium phosphate, ethylenediamine,glycine, N-methylpyrrolidine, pyridine, and 1,2-diaminocyclohexane andthe like.

The solvents include, for example, methanol, ethanol, THF, pyridine,collidine, dichloromethane, 1,2-dichloroethane, DMF, acetonitrile,1,4-dioxane, N,N-dimethylsulfoxide (DMSO), DMA, NMP, toluene, andhexamethylphosphoric triamide (HMPA). They are used alone or in mixturesand the like.

Step 3

Compound (III-c) wherein n2 is 0 can be manufactured by reactingcompound (III-a) in a solvent with compound (a-4) preferably in 1 to 10equivalent amount, for 5 minutes to 72 hours in the presence of a copperreagent preferably in 1 to 10 equivalent amount and a base in 1 to 10equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

Compound (a-4) can be obtained as a commercially available product, orby well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesisof organic compounds VI, Organic synthesis using metals” p. 97, Maruzen(2005)] or its equivalent methods.

Copper reagents include, for example, copper(0), copper(I) iodide,copper(II) acetate, copper(II) oxide, and copper(I) chloride and thelike.

The bases include, for example, potassium carbonate, cesium carbonate,lithium chloride, potassium chloride, potassium tert-butoxide, sodiumtert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodiumcarbonate, sodium hydroxide, potassium phosphate, ethylenediamine,glycine, N-methylpyrrolidine, pyridine, and 1,2-diaminocyclohexane andthe like.

The solvents include, for example, methanol, ethanol, THF, pyridine,collidine, dichloromethane, 1,2-dichloroethane, DMF, acetonitrile,1,4-dioxane, DMSO, DMA, NMP, toluene, and HMPA and the like. They areused alone or in mixtures.

Step 4

Compound (II-a) can be manufactured using compound (III-c) by a methodsimilar to step 1.

Step 5

Compound (III-d) can be manufactured by reacting compound (III-c) in asolvent with compound (a-5) preferably in 1 to 10 equivalent amount, for5 minutes to 72 hours at a temperature between −78° C. and the boilingpoint of the solvent used.

Compound (a-5) can be obtained as a commercially available product, orby well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesisof organic compounds VI, organic synthesis using metals” p. 59, Maruzen(2005)] or its equivalent methods.

The solvents include, for example, toluene, diethyl ether, THF, DME,1,4-dioxane, and hexane and the like. They are used alone or inmixtures.

Step 6

Compound (III-e) can be manufactured by reacting compound (III-d) in asolvent with an azidation reagent preferably in 1 equivalent to a largeexcess amount, for 5 minutes to 72 hours in the presence of, if needed,a base preferably in 1 equivalent to a large excess amount or if needed,an acid preferably in 1 equivalent to a large excess amount, at atemperature between 0° C. and the boiling point of the solvent used.

The azidation agents include, for example, sodium azide, potassiumazide, and diphenylphosphoryl azide and the like.

The bases include, for example, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium bicarbonate, triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, and1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and the like.

The acids include, for example, trifluoroacetic acid and the like.

The solvents include, for example, THF, DME, benzene, toluene, xylene,1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or inmixtures.

Step 7

Compound (II-b) can be manufactured by reacting compound (III-e) in asolvent with a reducing agent preferably in 1 to 10 equivalent amountfor 5 minutes to 72 hours at a temperature between −78° C. and theboiling point of the solvent used.

The reducing agents include, for example, lithium aluminum hydride,borane dimethyl sulfide complex, triphenylphosphine, and tetrabutyltinhydride and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, diethyl ether, THF, DME,1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or inmixtures.

Furthermore, as an alternative method, compound (II-b) can bemanufactured by reacting compound (III-e) in a solvent (i) with ahydrogen source preferably in 2 equivalents to a large excess amount for5 minutes to in 72 hours, or (ii) with hydrogen under the hydrogenatmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to72 hours, in the presence of a catalyst preferably in 0.01 to 50% byweight relative to compound (III-e), at a temperature between −20° C.and the boiling point of the solvent used.

The catalysts include, for example, palladium carbon, and palladiumhydroxide and the like.

The hydrogen sources include, for example, formic acid, amammoniumformate, sodium formate, cyclohexadiene, and hydrazine and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, and water and the like. They are used alone or in mixtures.

Step 8

Compound (III-f) can be manufactured using compound (III-c), forexample, by methods equivalent to a method described in “Jikken KagakuKoza 13, 5th Ed., Synthesis of organic compounds I, hydrocarbon/halogencompounds”, Maruzen (2005), “Jikken Kagaku Koza 15, 5th Ed., Synthesisof organic compounds III, aldehydes/ketones/quinones”, Maruzen (2005),and the like.

Compound (III-f) can be manufactured by reacting compound (III-c) in asolvent with 1 equivalent to a large excess amount of a halogenatingagent or an alkylating agent for 5 minutes to 72 hours at a temperaturebetween −78° C. and the boiling point of the solvent used.

The halogenating agents include, for example, (diethylamino)sulfurtrifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride,1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane-1,4-diiumtetrafluoroborate, N-chlorosuccinimide, N-bromosucciniide,N-iodosuccinimide, chlorine, bromine, and iodine and the like.

Alkylating agents include, for example, methyl iodide, ethyl iodide, andmethyl trifluoromethanesulfonate and the like.

The solvents include, for example, dichloromethane, 1,2-dichloroethane,and methanol and the like. They are used alone or in mixtures.

Step 9

Compound (II-c) can be manufactured by a method similar to step 1 usingcompound (III-f).

Step 10

Compound (III-g) can be manufactured by reacting compound (III-c) in asolvent with a reducing agent preferably in 1 to 10 equivalent amountfor 5 minutes to 72 hours at a temperature between −78° C. and theboiling point of the solvent used.

The reducing agents include, for example, lithium aluminum hydride,diisobutylaluminium hydride, bis(2-methoxyethoxy)aluminum sodiumhydride, borane dimethyl sulfide complex, lithium borohydride, andsodium borohydride and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, diethyl ether, THF, DME,1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or inmixtures.

Step 11

Compound (III-h) can be manufactured by reacting compound (III-g) in asolvent with a cyanating agent preferably in 1 to 10 equivalent amountfor 5 minutes to 72 hours in the presence of, if needed, an additivepreferably in 1 to 10 equivalent amount at a temperature between 0° C.and the boiling point of the solvent used.

The additives include, for example, zinc iodide and the like.

The cyanating agents include, for example, sodium cyanide, potassiumcyanide, tetrabutyl ammonium cyanide, and trimethylsilyl cyanide and thelike.

The solvents include, for example, dichloromethane, 1,2-dichloroethane,THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, and toluene and the like.They are used alone or in mixtures.

Step 12

Compound (II-d) can be manufactured by reacting compound (III-h) in asolvent with a reducing agent preferably in 1 to 10 equivalent amountfor 5 minutes to 72 hours at a temperature between 0° C. and the boilingpoint of the solvent used.

The reducing agents include, for example, lithium aluminum hydride, anddiborane and the like.

The solvents include, for example, toluene, diethyl ether, THF, DME,1,4-dioxane, and the like. They are used alone or in mixtures.

Furthermore, as an alternative method, compound (II-d) can bemanufactured by reacting compound (III-h) in a solvent or withoutsolvent (i) with a hydrogen source preferably in 2 equivalents to alarge excess amount for 5 minutes to 72 hours, or (ii) with hydrogenunder the hydrogen atmosphere preferably at 1 to 20 atmospheric pressurefor 5 minutes to 72 hours, by adding, if needed, an acid preferably in 1equivalent to a large excess amount or if needed, an ammonia-alcoholicsolution preferably in 1 equivalent to a large excess amount, in thepresence of a catalyst preferably in 0.01 to 50% by weight relative tocompound (III-h), at a temperature between −20° C. and the boiling pointof the solvent used (between 0° C. and 150° C. when without solvent).

The acids include, for example, acetic acid, and hydrochloric acid andthe like.

The ammonia-alcoholic solutions include, for example, anammonia-methanol solution, an ammonia-ethanol solution, and anammonia-2-propanol solution and the like.

The catalysts include, for example, palladium carbon, and Raney nickeland the like.

The hydrogen sources include, for example, formic acid, ammoniumformate, sodium formate, cyclohexadiene, and hydrazine and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, and water and the like. They are used alone or in mixtures.

Step 13

Compound (III-c) wherein n2 is 1 can be manufactured by reactingcompound (III-a) in a solvent with compound (a-6) preferably in 1 to 10equivalent amount, for 5 minutes to 72 hours in the presence of aphosphine compound preferably in 1 to 10 equivalent amount and an azocompound preferably in 1 to 10 equivalent amount, at a temperaturebetween −78° C. and the boiling point of the solvent used.

Compound (a-6) can be obtained as a commercially available product.

The phosphine compounds include, for example, triphenylphosphine, andtributylphosphine and the like.

The azo compounds include, for example, diethyl azodicarboxylate (DEAD),di-tert-butyl azadicarboxylate, diisopropyl azadicarboxylate,N,N,N′,N′-tetramethyl azadicarboxamide,1,1′-(azadicarbonyl)dipiperazine, and N,N,N′,N′-tetraisopropylazadicarboxamide and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like.They are used alone or in mixtures.

Furthermore, as an alternative method, compound (III-c) can bemanufactured by reacting compound (III-a) in a solvent with compound(a-7) preferably in 1 to 10 equivalent amount, in the presence of a basepreferably in 1 to 10 equivalent amount, at a temperature between −20°C. and the boiling point of the solvent used for 5 minutes to 72 hours.

Compound (a-7) can be obtained as a commercially available product.

The bases include, for example, sodium carbonate, potassium carbonate,potassium hydroxide, sodium hydroxide, potassium tert-butoxide,diisopropylethylamine, and DBU and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, andwater and the like. They are used alone or in mixtures.

Manufacturing Method 2

Among compounds (II), compound (II-i) that is a 3-aminochromanederivative wherein X is —O— can be manufactured according to thefollowing steps:

(wherein R², R^(2A), R⁵, X¹ and n2 are the same as the definitiondescribed above; R⁶ represents lower alkyl; and BOC representstert-butoxycarbonyl).Step 14

Compound (III-p) can be manufactured by reacting compound (III-o) in asolvent or without solvent with acrylonitrile preferably in 1 equivalentto a large excess amount, in the presence of a base preferably in 1 to10 equivalent amount, at a temperature between 0° C. and the boilingpoint of the solvent used (at 0° C. and 150° C. when without solvent)for 5 minutes to 72 hours.

Compound (III-o) can be obtained as a commercially available product, orby well-known methods (e.g., “Jikken Kagaku Koza 15, 5th Ed., Synthesisof organic compounds III, aldehydes/ketones/quinones” p. 78, Maruzen(2005)] or by its equivalent methods.

The bases include, for example, 1,4-diazabicyclo[2.2.2]octane and thelike.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF, and waterand the like. They are used alone or in mixtures.

Step 15

Compound (III-q) can be manufactured by treating compound (III-p) in asolvent with a base preferably in 1 equivalent to a large excess amount,for 5 minutes to 72 hours at a temperature between 0° C. and the boilingpoint of the solvent used.

The bases include, for example, potassium carbonate, lithium hydroxide,potassium hydroxide, sodium hydroxide, and sodium methoxide and thelike.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine andthe like. They are used by mixing with water, or mixing each solvent andfurther adding water thereto.

Step 16

Compound (III-r) can be manufactured by reacting compound (III-q) in asolvent or without solvent with an azidation reagent preferably in 1equivalent to a large excess amount and tert-butanol preferably in 1equivalent to a large excess amount, in the presence of, if needed, abase preferably in 1 equivalent to a large excess amount, at atemperature between 0° C. and the boiling point of the solvent used(between 0° C. and 150° C. when without solvent) for 5 minutes to 72hours.

The azidation reagents include, for example, sodium azide, potassiumazide, and diphenylphosphoryl azide and the like.

The bases include, for example, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium bicarbonate, triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and thelike.

The solvents include, for example, THF, DME, benzene, toluene, xylene,1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or inmixtures.

Step 17

Compound (III-s) can be manufactured by reacting compound (III-r) in asolvent (i) with hydrogen under the hydrogen atmosphere preferably at 1to 20 atmospheric pressure for 5 minutes to 72 hours, or (ii) with ahydrogen source preferably in 2 equivalent to a large excess amount for5 minutes to 72 hours, in the presence of preferably 0.01 to 50% byweight of a catalyst, at a temperature between −20° C. and the boilingpoint of the solvent used.

The catalysts include, for example, palladium carbon, palladium,palladium hydroxide, palladium acetate, and palladium black and thelike.

The hydrogen sources include, for example, formic acid, ammoniumformate, sodium formate, cyclohexadiene, and hydrazine and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, and water and the like. They are used alone or in mixtures.

Step 18

Compound I can be manufactured by treating compound (III-s) in a solventor without solvent with an additive preferably in 1 equivalent to alarge excess amount, at a temperature between 0° C. and the boilingpoint of the solvent used (between 0° C. and 150° C. when withoutsolvent), or if needed, using a microwave reaction device and at atemperature between 0° C. and 200° C., for one minute to 72 hours.

The additives include, for example, pyridine hydrochloride, borontribromide, boron trifluoride diethyl ether complex, and aluminumchloride and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are usedalone or in mixtures.

Step 19

Compound (II-i) wherein n2 is 1 can be manufactured using compounds(III-t) and (a-6) by a method similar to step 13.

Step 20

Compound (II-i), wherein n2 is 0 and R² is optionally substituted arylor optionally substituted aromatic heterocyclic group, can bemanufactured using compounds (III-t) and (a-3) by a method similar tostep 2.

Manufacturing Method 3

Among compounds (III-r) described in manufacturing method 2, compound(III-r-2) can be also manufactured according to the following step:

(wherein R^(5A) represents chlorine atom, bromine atom, iodine atom,p-toluene sulfonyloxy, methanesulfonyloxy ortrifluoro-methanesulfonyloxy, and the like; R⁶ is the same as thedefinition described above; and R⁷ represents lower alkyl in R⁵).Step 21

Compound (III-r-2) can be manufactured by reacting compound (III-r-1) ina solvent with compound (a-8) preferably in 1 to 5 equivalent amount,for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to10 equivalent amount and a palladium catalyst preferably in 0.001 to 0.5equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

Compound (III-r-1) can be obtained according to step 16 of manufacturingmethod 2.

Compound (a-8) can be obtained as a commercially available product, orby well-known methods [e.g., Jikken Kagaku Koza 18, 5th Ed., Synthesisof organic compounds VI, Organic synthesis using metals” p. 97, Maruzen(2005)] or by its equivalent methods.

The bases include, for example, sodium carbonate, potassium carbonate,potassium phosphate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, and DBU and the like.

The palladium catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium, and1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, and water and the like. They are used alone or in mixtures.

Manufacturing Method 4

Among compounds (II), compound (II-j), that is a 3-aminochroman-4-onederivative, can be manufactured according to the following steps:

(wherein R², R⁵, n2 and E¹ are each the same as the definition describedabove; R⁸ represents phenyl optionally substituted with a substituentselected from the group consisting of fluorine atom, chlorine atom,bromine atom, iodine atom, lower alkyl and lower alkoxy; and X³represents chlorine atom, bromine atom or iodine atom).Step 22

Compound (IV-a) can be manufactured by reacting compound (III-c)obtained in step 3 or step 13 of manufacturing method 1 in a solventwith hydroxylamine or a salt thereof preferably in 1 to 10 equivalentamount, for 5 minutes to 72 hours in the presence of a base or acidpreferably in 1 to 10 equivalent amount, at a temperature between −20°C. and the boiling point of the solvent used.

The bases include, for example, potassium carbonate, potassiumphosphate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, and DBU and the like.

The acids include, for example, hydrochloric acid, and acetic acid andthe like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, acetonitrile, acetone, diethylether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and thelike. They are used alone or in mixtures.

The hydroxylamine or salts thereof include, for example, hydroxylamine,hydroxylamine hydrochloride, and hydroxylamine sulfate and the like.Also, an aqueous hydroxylamine solution can be used.

Step 23

Compound (IV-b) can be manufactured by reacting compound (IV-a) in asolvent with compound (a-9) preferably in 1 to 10 equivalent amount, for5 minutes to 72 hours in the presence of a base preferably in 1 to 10equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

Compound (a-9) can be obtained as a commercially available product.

The bases include, for example, potassium carbonate, potassiumhydroxide, sodium hydroxide, sodium bicarbonate, sodium hydride, sodiummethoxide, potassium tert-butoxide, triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and thelike.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,acetone, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine,and water and the like. They are used alone or in mixtures.

Step 24

Compound (II-j) can be manufactured by treating compound (IV-b) in asolvent with a base preferably in 1 to 10 equivalent amount for 5minutes to 72 hours at a temperature between −20° C. and the boilingpoint of the solvent used.

The bases include, for example, potassium hydroxide, sodium hydroxide,sodium methoxide, sodium ethoxide, potassium methoxide, potassiumethoxide, potassium tert-butoxide, and pyridine and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,acetone, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, andpyridine and the like. They are used by mixing with water or mixing eachsolvent and further adding water thereto.

Manufacturing Method 5

Among compounds (II), compound (II-k), that is a5,6,7,8-tetrahydroquinoline derivative, can be manufactured according tothe following steps:

[wherein R², R^(2A), X² and n2 each are the same as the definitiondescribed above; in R², R^(2B) represents (i) optionally substitutedcycloalkyl, or (ii) aliphatic heterocyclic group wherein X⁴ is bonded tothe sp³ carbon constituting the aliphatic heterocyclic group amongoptionally substituted aliphatic heterocyclic groups; X⁴ representsleaving group such as chlorine atom, bromine atom, iodine atom,p-toluene sulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy, or the like; represents the substituentmentioned above as a substituent of optionally substituted heterocyclicdiyl or hydrogen atom; and R¹¹ and R¹² are the same or different, andeach represents hydrogen atom or lower alkyl].Step 25

Compound (V-b) can be manufactured by reacting compound (V-a) in asolvent with compound (a-10) preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours in the presence of an additive preferably in0.1 to 10 equivalent amount, at a temperature between −20° C. and theboiling point of the solvent used.

The additives include, for example, pyridinium p-toluenesulfonate,p-toluenesulfonic acid, hydrochloric acid, and acetic acid and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, and acetonitrile and thelike.

Compound (V-a) can be obtained as a commercially available product, orby well-known methods (e.g., Synthetic Communications, 2010 Vol. 40, p.1708-1716) or its equivalent methods.

Compound (a-10) can be obtained as a commercially available product.Other than the methods above, compound (V-b), for example, can bemanufactured by methods equivalent to a method described in ProtectiveGroups in Organic Synthesis, the third edition, by T. W. Greene, JohnWiley & Sons Inc. (1999) and the like.

Step 26

Compound (V-c) can be manufactured by reacting compound (V-b) in asolvent with an oxidizing agent preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours at a temperature between −20° C. and theboiling point of the solvent used.

The oxidizing agents include, for example m-chloroperoxybenzoic acid(m-CPBA), benzoyl peroxide, peracetic acid, and hydrogen peroxide andthe like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and thelike. They are used alone or in mixtures.

Steps 27-1 and 27-2

Compound (V-d) can be manufactured by the following method.

Step 27-1

Compound (V-c) is subjected to a reaction in a solvent with an acidanhydride preferably in 1 to 10 equivalent amount, for 5 minutes to 72hours in the presence of a base preferably in 1 to 10 equivalent amount,at a temperature between −78° C. and the boiling point of the solventused.

Step 27-2

The compound obtained in step 27-1 is subjected to a reaction in asolvent with a base in 1 equivalent to a large excess amount relative tocompound (V-c) for 5 minutes to 72 hours at a temperature between 0° C.and the boiling point of the solvent used.

The acid anhydrides include acetic anhydride, and trifluoroacetic acidanhydride and the like.

The bases used in steps 27-1 and 27-2 are the same or different, andeach include, for example, potassium carbonate, potassium hydroxide,sodium hydroxide, triethylamine, diisopropylethylamine,N-methylmorpholine, and pyridine and the like.

The solvents used in step 27-1 are the same or different, and eachinclude, for example, dichloromethane, chloroform, 1,2-dichloroethane,toluene, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, pyridine and the like. They are used alone or in mixtures.

The solvents used in step 27-2 are the same or different, and eachinclude, for example, methanol, ethanol, dichloromethane, chloroform,1,2-dichloroethane, toluene, acetonitrile, diethyl ether, THF, DME,1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They areused alone or in mixtures.

Step 28

Compound (V-e), wherein n2 is 0 and R² is optionally substituted aryl oroptionally substituted aromatic heterocyclic group, can be manufacturedby reacting compound (V-d) in a solvent with compound (a-11) preferablyin 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presenceof a phosphine compound preferably in 1 to 10 equivalent amount and anazo compound preferably in 1 to 10 equivalent amount, at a temperaturebetween −78° C. and the boiling point of the solvent used.

Compound (a-11) can be obtained as a commercially available product.

The phosphine compounds include, for example, triphenylphosphine, andtributylphosphine and the like.

The azo compounds include, for example, DEAD, di-tert-butylazadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethylazadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine, andN,N,N′,N′-tetraisopropyl azadicarboxamide and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like.They are used alone or in mixtures.

Step 29

Compound (V-e) wherein n2 is 1 can be manufactured by reacting compound(V-d) in a solvent with compound (a-7) preferably in 1 to 10 equivalentamount, for 5 minutes to 72 hours in the presence of a base preferablyin 1 to 10 equivalent amount, at a temperature between −20° C. and theboiling point of the solvent used.

Compound (a-7) can be obtained as a commercially available product.

The bases include, for example, sodium carbonate, potassium carbonate,cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride,potassium tert-butoxide, diisopropylethylamine, and DBU and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, DMF, 1,4-dioxane, and water and the like. Theyare used alone or in mixtures.

Compound (V-e) wherein n2 is 0 and R² is optionally substitutedcycloalkyl, or compound (V-e) wherein n2 is 0 and R² is optionallysubstituted aliphatic heterocyclic group wherein the sp^(a) carbonconstituting the aliphatic heterocyclic group is bonded to —O—, can bemanufactured by reacting compound (V-d) in a solvent with compound(a-12) preferably in 1 to 10 equivalent amount, in the presence of abase preferably in 1 to 10 equivalent amount at a temperature between−20° C. and the boiling point of the solvent used for 5 minutes to 72hours.

Compound (a-12) can be obtained as a commercially available product.

The bases include, for example, sodium carbonate, potassium carbonate,cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride,potassium tert-butoxide, diisopropylethylamine, and DBU and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, DMF, 1,4-dioxane, and water and the like. Theyare used alone or in mixtures.

Step 30

Compound (V-f) can be manufactured using compound (V-e), for example, bymethods equivalent to a method described in Protective Groups in OrganicSynthesis, third edition by T. W. Greene, John Wiley & Sons Inc. (1999),and the like.

Step 31

Compound (II-k) can be manufactured using compound (V-f) by a methodsimilar to step 1.

Manufacturing Method 6

Among compounds (II-k), compound (II-L) wherein in the position 2 of5,6,7,8-tetrahydroquinoline is lower alkoxy or —NR^(c)R^(d) [whereinR^(c) and R^(d) are the same or different, and each represent hydrogenatom or low alkyl, or form an optionally substituted nitrogen-containingheterocyclic group together with the adjacent nitrogen atom (thenitrogen-containing heterocyclic groups include, for example,aziridinyl, azetidinyl, pyrrolidinyl, piperidine, azepanyl, pyrrolyl,imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl,thioxazolidinyl, 2H-thioxazolyl, morpholino, and thiomorpholinyl and thelike; and the substituents of the optionally substitutednitrogen-containing heterocyclic group together with the adjacentnitrogen atom are the same or different, and each include, for example,the substituent exemplified as the substituent of the aliphaticheterocyclic group optionally substituted with the number ofsubstitution of 1-3)] can also be manufactured according to thefollowing steps:

(wherein R² and n2 are the same as the definition described above;R^(10A) corresponds to R¹⁰ of compound (V-f), and represents fluorineatom, chlorine atom, bromine atom or iodine atom in R¹⁰, R¹³ representslower alkoxy or —NR^(c)R^(d) [wherein R^(c) and R^(d) each are the sameas the definition described above] in R¹⁰).Step 32

Compound (V-f-2) can be manufactured by reacting compound (V-f-1) in asolvent with compound (a-13) or an alkali metal salt of compound (a-13)preferably in 1 to 10 equivalent amount, in the presence of, if needed,a base preferably in 1 to 10 equivalent amount, at a temperature between0° C. and the boiling point of the solvent used, or if needed, using amicrowave reaction device and at a temperature between 0° C. and 200° C.for one minute to 72 hours.

The bases include, for example, potassium carbonate, potassiumhydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide,triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, andDBU and the like.

Compound (V-f-1) can be obtained according to step 30 of manufacturingmethod 5. Compound (a-13) or an alkali metal salt of compound (a-13) canbe obtained as a commercially available product.

The alkali metal salts of compound (a-13) include, for example, lithiumsalt, sodium salt or potassium salt or the like of compound (a-13).

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and waterand the like. They are used alone or in mixtures.

Step 33

Compound (II-L) can be manufactured using compound (V-f-2) by a methodsimilar to step 1.

Manufacturing Method 7

Among compounds (II), compounds (II-m), (II-n) and (II-o) can bemanufactured according to the following steps:

(wherein A^(A) represents heterocyclic diyl wherein X⁵ is bonded to thesp² carbon constituting the heterocyclic diyl in the optionallysubstituted heterocyclic diyl; R² and n2 each are the same as thedefinition described above; R¹⁴ represents amino, nitro or cyano; and X⁵represents fluorine atom, chlorine atom, bromine atom or iodine atom).Step 34

Compound (II-m) can be manufactured by reacting compound (VII-a) in asolvent or without solvent with compound (a-6) preferably in 1 to 10equivalent amount for one minute to 72 hours, if needed, in the presenceof sodium iodide or potassium iodide preferably in 1 to 10 equivalentamount, and if needed, in the presence of a base preferably in 1 to 10equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used (between −20° C. and 180° C. when withoutsolvent), or if needed, using a microwave reaction device and at atemperature between 0° C. and 200° C.

Compound (VII-a) can be obtained as a commercially available product ormanufactured by methods equivalent to a method described in well-knownmethods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, JohnWiley & Sons Inc. (2008), CN101983961A, WO2007/036743, and the like].

Compound (a-6) can be obtained as a commercially available product.

The bases include, for example, potassium carbonate, cesium carbonate,potassium hydroxide, sodium hydroxide, potassium tert-butoxide,triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, andDBU and the like.

The solvents include, for example, toluene, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like.They are used alone or in mixtures.

Furthermore, as an alternative method, when reacting with compound(a-6), wherein n2 is 0 and R² is an optionally substituted aromaticheterocyclic group or optionally substituted aryl, a method similar tostep 2 of manufacturing method 1 can be used.

Step 35

Compound (II-n) can be manufactured by reacting compound (II-m), whereinR¹⁴ is nitro, in a solvent, (i) with hydrogen under the hydrogenatmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to72 hours, or (ii) with a hydrogen source preferably 2 equivalent to alarge excess amount relative to compound (II-m) for 5 minutes to 72hours, in the presence of a catalyst preferably in 0.01 to 50% byweight, at a temperature between −20° C. and the boiling point of thesolvent used.

The catalysts include, for example, palladium carbon, palladium,palladium hydroxide, palladium acetate, palladium black, platinum oxide,and Raney nickel and the like.

The hydrogen sources include, for example, formic acid, ammoniumformate, sodium formate, cyclohexadiene, and hydrazine and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and waterand the like. They are used alone or in mixtures.

Furthermore, as an alternative method, compound (II-n) can bemanufactured by reacting compound (II-m) in a solvent with a metal ormetal salt preferably in 1 to 10 equivalent amount, in the presence ofan additive preferably in 1 equivalent to large excess amount, at atemperature between 0° C. and the boiling point of the solvent used for5 minutes to 72 hours.

The metals or metal salts include, for example, tin, zinc, iron,samarium, indium, and tin dichloride and the like.

The additives include, for example, hydrochloric acid, acetic acid, andammonium chloride and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, and water and the like. They are used alone or in mixtures.

Step 36

Compound (II-o) can be manufactured using compound (II-m) wherein R¹⁴ iscyano by a method similar to step 12.

Manufacturing Method 8

Among compounds (II), compound (II-n) can also be manufactured accordingto the following steps:

(wherein A^(A), R², R^(2A), X¹ and n2 are each the same as thedefinition described above).Step 37

Compound (II-n) wherein n2 is 1 can be manufactured by reacting compound(VIII-a) in a solvent with compound (a-6) preferably in 1 to 10equivalent amount, for 5 minutes to 72 hours in the presence of aphosphine compound preferably in 1 to 10 equivalent amount and an azocompound preferably in 1 to 10 equivalent amount, at a temperaturebetween −78° C. and the boiling point of the solvent used.

Compound (a-6) can be obtained as a commercially available product.

Compound (VIII-a) can be obtained as a commercially available product ormanufactured by methods equivalent to a method described in well-knownmethods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, JohnWiley & Sons Inc. (2008), WO2011/025546, and the like].

The phosphine compounds include, for example, triphenylposphine, andtributylphosphine and the like.

The azo compounds include, for example, DEAD, di-tert-butylazadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethylazadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine, andN,N,N′,N′-tetraisopropyl azadicarboxamide and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like.They are used alone or in mixtures.

Step 38

Compound (II-n) wherein n2 is 0 and R² is optionally substituted aryl oroptionally substituted aromatic heterocyclic group can be manufacturedby a method similar to step 2 of manufacturing method 1 using compounds(VIII-a) and (a-3).

Compound (VIII-a) can be obtained in the method similar to the above.

Compound (a-3) can be obtained as a commercially available product.

Manufacturing Method 9

Among compounds (II), compound (II-n) can also be manufactured accordingto the following steps:

(wherein A^(A), R², R^(2A), R^(2B), X¹, X², X⁴ and n2 are each the sameas the definition described above).Step 39

Compound (IX-b) wherein n2 is 1 can be manufactured by reacting compound(IX-a) in a solvent with compound (a-7) preferably in 1 to 10 equivalentamount, for 5 minutes to 72 hours in the presence of a base preferablyin 1 to 10 equivalent amount, at a temperature between −20° C. and theboiling point of the solvent used.

Compound (a-7) can be obtained as a commercially available product.

Compound (IX-a) can be obtained as a commercially available product ormanufactured by methods equivalent to a method described in well-knownmethods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, JohnWiley & Sons Inc. (2008), and the like].

The bases include, for example, sodium carbonate, potassium carbonate,cesium carbonate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, diisopropylethylamine, and DBU and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, DMF, 1,4-dioxane, water,and the like. They are used alone or in mixtures.

Compound (IX-b) wherein n2 is 0 and R² is optionally substitutedcycloalkyl, or compound (IX-b) wherein n2 is 0 and R² is optionallysubstituted aliphatic heterocyclic group wherein the sp^(a) carbonconstituting the aliphatic heterocyclic group is bonded to —O—, can bemanufactured by reacting compound (IX-a) in a solvent with compound(a-12) preferably in 1 to 10 equivalent amount, in the presence of abase preferably in 1 to 10 equivalent amount, at a temperature between−20° C. and the boiling point of the solvent used for 5 minutes to 72hours.

Compound (a-12) can be obtained as a commercially available product.

The bases include, for example, sodium carbonate, potassium carbonate,cesium carbonate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, diisopropylethylamine, and DBU and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, DMF, 1,4-dioxane, andwater and the like. They are used alone or in mixtures.

Step 40

Compound (IX-b), wherein n2 is 0 and R² is optionally substituted arylor optionally substituted aromatic heterocyclic group, can bemanufactured using compounds (IX-a) and (a-3) by a method similar tostep 2 of manufacturing method 1.

Step 41

Compound (II-n) can be manufactured by a method similar to step 34 usingcompound (IX-b).

Manufacturing Method 10

Compound (I) can be manufactured according to the followingmanufacturing method.

(wherein R¹, R², X, n1, n2 and A are each the same as the definitiondescribed above, and the wavy line part between R¹ and the adjacentcarbon atom represents cis or trans configuration).Step 42

Compound (I) can be manufactured by reacting compound (II) in a solventwith compound (a-1) preferably in 1 to 5 equivalent amount, for 5minutes to 72 hours in the presence of a condensation agent preferablyin 1 to 5 equivalent amount, and if needed, in the presence of anadditive preferably in 1 to 5 equivalent amount, at a temperaturebetween −20° C. and the boiling point of the solvent used.

Compound (a-1) can be obtained as a commercially available product oralso manufactured by methods equivalent to a method described inwell-known methods [e.g., “Jikken Kagaku Koza 16, 5th Ed., Synthesis oforganic compounds IV, carboxylic acid, amino acid, peptide” Maruzen(2005), and the like].

Compound (II) can be manufactured according to any one of manufacturingmethods 1, 2, 4-9, 11-15, 17-19, and 21-28.

The condensation agents include, for example, 1,3-dicyclohexanecarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDC), carbonyldiimidazole (CDT), and 2-chloro-1-methylpyridinium iodide and the like.

The additives include, for example, 1-hydroxybenzotriazole monohydrate(HOBt) and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine andthe like. They are used alone or in mixtures.

Furthermore, as an alternative method, compound (I) can be manufacturedby reacting compound (II) in a solvent or without solvent with compound(a-2) preferably in 1 to 10 equivalent amount, if needed, in thepresence of a base preferably in 1 to 10 equivalent amount, at atemperature between −20° C. and the boiling point of the solvent used(between −20° C. and 150° C. when without solvent) for 5 minutes to 72hours.

Compound (a-2) can be obtained as a commercially available product, orobtained by well-known methods [e.g., “Jikken Kagaku Koza 16, 5th Ed.,Synthesis of organic compounds IV” p. 101, Maruzen (2005)] or by itsequivalent methods.

The bases include, for example, potassium carbonate, potassiumhydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, DBU, and4-dimethylaminopyridine (DMAP) and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. Theyare used alone or in mixtures.

Manufacturing Method 11

Among compounds (II), compound (II-p), (II-q) or (II-r) as a5-aminochromane derivative or a 5-aminomethylchromane derivative can bemanufactured according to the following steps:

(wherein R², R^(2A), R¹⁴, X¹, X², X⁵, n2 and E¹ are the same as thedefinition described above; and X⁶ represents hydroxy, fluorine atom,chlorine atom, bromine atom or iodine atom).Step 43

Compound (X-b) can be manufactured by reacting compound (X-a) in asolvent or without solvent, (i) with 1 equivalent to a large excessamount of a reducing agent for 5 minutes to 72 hours in the presence of1 equivalent to a large excess amount of an acid at a temperaturebetween −20° C. and the boiling point of the solvent used, or (ii) withhydrogen under the hydrogen atmosphere at 1 to 20 atmospheric pressureor with 2 equivalents to a large excess amount of a hydrogen source for5 minutes to 72 hours in the presence of a catalyst preferably in 0.01to 50% by weight, at a temperature between −20° C. and the boiling pointof the solvent used.

Compound (X-a) can be obtained as a commercially available product, orobtained by well-known methods [Chemistry of Heterocyclic Compounds,Volume 31, John Wiley & Sons Inc. (2008) and the like] or theirequivalent methods.

The acids include, for example, acetic acid, hydrochloric acid, andtrifluoroacetic acid and the like.

The reducing agents include, for example, triethylsilane, and zincamalgam and the like.

The catalysts include, for example, palladium carbon, palladium,palladium hydroxide, palladium acetate, palladium black, platinum oxide,and Raney nickel and the like.

The hydrogen sources include, for example, formic acid, ammoniumformate, sodium formate, cyclohexadiene, and hydrazine and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and waterand the like. They are used alone or in mixtures.

Step 44

Compound (II-p) wherein n2 is 0 can be manufactured using compound (X-b)wherein X⁶ is hydroxy by a method similar to step 2 or 3 ofmanufacturing method 1.

Step 45

Compound (II-p) wherein n2 is 1 can be manufactured by a method similarto step 13 of manufacturing method 1 using compound (X-b) wherein X⁶ ishydroxy.

Step 46

Compound (II-p) can be manufactured by a method similar to step 34 usingcompound (X-b) wherein X⁶ is fluorine atom, chlorine atom, bromine atomor iodine atom.

Step 47

Compound (II-q) can be manufactured by a method similar to step 35 usingcompound (II-p) wherein R¹⁴ is nitro.

Step 48

Compound (II-r) can be manufactured by a method similar to step 12 usingcompound (II-p) wherein R¹⁴ is cyano.

Manufacturing Method 12

Among compounds (II), compound (II-s) that is a5,6,7,8-tetrahydroquinoline derivative can be manufactured according tothe following steps:

(wherein R², R^(10A) and n2 are the same as the definition describedabove).Step 49

Compound (V-g) can be manufactured by a method similar to step 34 ofmanufacturing method 7 using compound (V-a-1).

Compound (V-a-1) can be obtained as a commercially available product, orby well-known methods [e.g., Synthetic Communications, 2010 Vol. 40, p.1708-1716] or its equivalent methods.

Step 50

Compound (II-s) can be manufactured by a method similar to step 1 ofmanufacturing method 1 using compound (V-g).

Manufacturing Method 13

Among compounds (II), compound (II-t) that is a5,6,7,8-tetrahydroisoquinoline derivative can be manufactured accordingto the following steps:

(wherein R², R^(2A), R^(2B), R⁵, X², X⁴ and n2 are the same as thedefinition described above).Step 51

Compound (XI-b), wherein n2 is 0 and R² is optionally substituted arylor optionally substituted aromatic heterocyclic group, can bemanufactured by a method similar to step 28 of manufacturing method 5using compound (XI-a).

Compound (XI-a) can be obtained as a commercially available product orby well-known methods [e.g., US2013/0274287, WO2013/079452 and the like]or its equivalent methods.

Step 52

Compound (XI-b) wherein n2 is 1 and R² is optionally substitutedcycloalkyl or optionally substituted aliphatic heterocyclic group, andcompound (XI-b) wherein n2 is 0 and R² is optionally substitutedcycloalkyl, or compound (XI-b) wherein n2 is 0 and R² is aliphaticheterocyclic group wherein the sp³ carbon constituting the aliphaticheterocyclic group is bonded to —O—, can be manufactured by a methodsimilar to step 29 of manufacturing method 5 using compound (XI-a).

Step 53

Compound (XI-c) can be manufactured by a method similar to step 26 ofmanufacturing method 5 using compound (XI-b).

Steps 54-1 and 54-2

Compound (XI-d) can be manufactured by a method similar to steps 27-1and 27-2 of manufacturing method 5 using compound (XI-c).

Step 55

Compound (XI-e) can be manufactured by treating compound (XI-d) in asolvent with an oxidation agent preferably in 1 to 10 equivalent amountfor 5 minutes to 72 hours at a temperature between −20° C. and theboiling point of the solvent used.

The oxidizing agent includes, for example, manganese dioxide, chromicacid, pyridinium chlorochromate (PCC), pyridinium dichlorochromate(PDC), potassium permanganate, sulfur trioxide-pyridine, axone(registered trademark), DMSO/oxalyl chloride, and cess-Martinperiodinane and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine, hydrochloric acid,acetic acid, propionic acid, acetic anhydride, sulfuric acid, and waterand the like. They are used alone or in mixtures.

Step 56

Compound (II-t) can be manufactured by a method similar to step 1 ofmanufacturing method 1 using compound (XI-e).

Manufacturing Method 14

Among compounds (II), compounds (II-u), (II-v), (II-w), (II-x) and(II-y), wherein X is —O—, —S—, —NR^(X1)— (wherein R^(X1) representshydrogen atom or lower alkyl), —CH═CH—, —NH—CO— or —SO₂—; and X isbonded to the sp³ carbon constituting A; can be manufactured accordingto the following steps:

[wherein R², R¹⁴ and n2 are the same as the definition described above;A^(B) represents heterocyclic diyl wherein X⁷ is bonded to the sp³carbon constituting the heterocyclic diyl among optionally substitutedheterocyclic diyl groups; X⁷ represents fluorine atom, chlorine atom,bromine atom, iodine atom, p-toluene sulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy; X^(A) represents —O—, —S— or —NR^(X1)—(wherein R^(X1) represents hydrogen atom or lower alkyl); and X^(B)represents —O—, —S—, —NR^(X1)— (wherein R^(X1) represents hydrogen atomor lower alkyl), —CH═CH— or —NH—CO—)].Step 57

Compound (II-u) wherein X^(B) is X^(A) can be manufactured by a methodsimilar to step 29 of manufacturing method 5 using compounds (XII-a) and(a-6a).

Compound (XII-a) can be obtained as a commercially available product ormanufactured by methods equivalent to a method described in well-knownmethods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, JohnWiley & Sons Inc. (2008), and the like].

Compound (a-6a) can be obtained as a commercially available product.

Step 58

Compound (II-u) wherein X^(B) is —NH—CO— can be manufactured by reactingcompound (XII-a) in a solvent with compound (a-14) preferably in 1 to 10equivalent amount under exposure of light, for 5 minutes to 72 hours inthe presence of a copper reagent preferably in 0.01 to 1 equivalentamount and a base preferably in 1 to 10 equivalent amount at atemperature between −20° C. and the boiling point of the solvent used.

The copper reagents include, for example, copper(0), copper(I) iodide,copper(II) acetate, copper(II) oxide, and copper(I) chloride and thelike.

The bases include, for example, potassium carbonate, cesium carbonate,potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide,and potassium phosphate and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, DMF, HMPA, DMSO, 1,4-dioxane, and water and thelike. They are used alone or in mixtures.

Compound (a-14) can be obtained as a commercially available product.

Step 59

Compound (II-u) wherein X^(B) is —CH═CH— can be manufactured by reactingcompound (XII-a) in a solvent with compound (a-15) preferably in 1 to 5equivalent amount, for 5 minutes to 72 hours in the presence of a basepreferably in 0.1 to 10 equivalent amount and a metallic catalystpreferably 0.001 to 0.5 equivalent amount at a temperature between −20°C. and the boiling point of the solvent used.

Compound (a-15) can be obtained as a commercially available product orby well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesisof organic compounds VI, Organic synthesis using metals” p. 97, Maruzen(2005)], or its equivalent methods.

The bases include, for example, potassium carbonate, potassiumphosphate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, DBU, and sodium hexamethyldisilazide and the like.

The metallic catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct, nickel dicyclooctadiene, nickel chloride, nickel bromide,and nickel iodide and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and thelike. They are used alone or in mixtures.

Step 60

Compound (II-v) can be manufactured by a method similar to step 35 ofmanufacturing method 7 using compound (II-u) wherein R¹⁴ is nitro.

Step 61

Compound (II-w) can be manufactured by a method similar to step 12 ofmanufacturing method 1 using compound (II-u) wherein R¹⁴ is cyano.

Step 62

Compound (II-x) can be manufactured by treating compound (II-v) whereinX⁶ is —S— in a solvent with an oxidizing agent preferably in 2 to 10equivalent amount for 5 minutes to 72 hours at a temperature between 0°C. and the boiling point of the solvent used.

The oxidizing agents include, for example, m-chloroperoxybenzoic acid,benzoyl peroxide, peracetic acid, hydrogen peroxide solution, sodiumperiodate, and potassium permanganate and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and waterand the like. They are used alone or in mixtures.

Step 63

Compound (II-y) can be manufactured by a method similar to step 62 usingcompound (II-w) wherein X⁶ is —S—.

Manufacturing Method 15

Among compounds (II), compounds (II-z), (II-A), (II-B), (II-C) and(II-D), wherein X is —O—, —S—, —NR^(X1)— (wherein R^(X1) representshydrogen atom or lower alkyl), —CH═CH—, —NH—CO— or —SO₂—; and X isbonded to the sp² carbon constituting A; can be manufactured accordingto the following steps:

(wherein R², R¹⁴, X⁷, X^(A), X^(B) and n2 are the same as the definitiondescribed above; A^(c) represents a heterocyclic diyl wherein X⁷ isbonded to the sp² carbon constituting the heterocyclic diyl among theoptionally substituted heterocyclic diyl groups).Step 64

Compound (II-u) wherein X^(B) is X^(A) can be manufactured by a methodin similar to step 34 using compounds (XII-b) and (a-6a).

Compound (XII-b) can be obtained as a commercially available product, ormanufactured by methods equivalent to a method described in well-knownmethods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, JohnWiley & Sons Inc. (2008), and the like].

Step 65

Compound (II-z) wherein X^(B) is —NH—CO— can be manufactured by reactingcompound (XII-b) in a solvent with compound (a-14) preferably in 1 to 10equivalent amount, for 5 minutes to 72 hours in the presence of a copperreagent preferably 0.01 to 1 equivalent amount or palladium catalyst in0.001 to 0.5 equivalent amount, a ligand preferably in 0.001 to 1equivalent amount and a base preferably in 1 to 10 equivalent amount ata temperature between −20° C. and the boiling point of the solvent used.

The copper reagents include, for example, copper(0), copper(I) iodide,copper(II) acetate, copper(II) oxide, and copper(I) chloride and thelike.

The palladium catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium, and1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct and the like.

The ligands include, for example, phenanthroline, trans-1,2-cyclohexanediamine, picolinic acid, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,o-tolylphosphine, tributylphosphine, di-tert-butydiphenylphosphine,2-(di-tert-butylphosphino)biphenyl, and2-(dicyclohexylphosphino)biphenyl and the like.

The bases include, for example, potassium carbonate, cesium carbonate,potassium phosphate, potassium tert-butoxide, sodium tert-butoxide,sodium disilazide, triethylamine, potassium acetate, sodium ethoxide,sodium carbonate, sodium hydroxide, potassium phosphate,ethylenediamine, glycine, N-methylpyrrolidine, pyridine, and1,2-diaminocyclohexane and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, DMF, HMPA, DMSO, 1,4-dioxane, and water and thelike. They are used alone or in mixtures.

Step 66

Compound (II-z) wherein X^(B) is —CH═CH— can be manufactured by reactingin a solvent compound (XII-b) with compound (a-15) preferably in 1 to 5equivalent amount, for 5 minutes to 72 hours in the presence of a basepreferably in 0.1 to 10 equivalent amount and a palladium catalystpreferably in 0.001 to 0.5 equivalent amount at a temperature between−20° C. and the boiling point of the solvent used.

The bases include, for example, potassium carbonate, potassiumphosphate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, and DBU and the like.

The palladium catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium, and1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and thelike. They are used alone or in mixtures.

Step 67

Compound (II-A) can be manufactured by a method similar to step 35 ofmanufacturing method 7 using compound (II-z) wherein R¹⁴ is nitro.

Step 68

Compound (II-B) can be manufactured by a method similar to step 12 ofmanufacturing method 1 using compound (II-z) wherein R¹⁴ is cyano.

Step 69

Compound (II-C) can be manufactured by a method similar to step 62 ofmanufacturing method 14 using compound (II-A) wherein X^(B) is —S—.

Step 70

Compound (II-D) can be manufactured by a method similar to step 62 ofmanufacturing method 14 using compound (II-B) wherein X^(B) is —S—.

Manufacturing Method 16

Among compounds (XII-a) and (XII-b), compound (XII-d) wherein X⁷ isp-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy,can be manufactured according to the following step:

(wherein A and R¹⁴ are the same as the definition described above;X^(7A) represents p-toluenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy).Step 71

Compound (XII-d) can be manufactured by treating compound (XII-c) in asolvent or without solvent with a sulfonylation agent preferably in 1 to10 equivalent amount, for 5 minutes to 72 hours if needed, in thepresence of a base preferably in the equal amount of a catalyst to 10equivalent amount at a temperature between −20° C. and 150° C.

The sulfonylation agents include, for example, trifluoromethanesulfonicanhydride, methanesulfonic anhydride, methanesulfonyl chloride, andp-toluenesulfonyl chloride and the like.

The bases include, for example, triethylamine, diisopropylethylamine,and pyridine and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. Theyare used alone or in mixtures.

Compound (XII-c) can be obtained as a commercially available product, oralso manufactured by methods equivalent to a method described inwell-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume1-64, John Wiley & Sons Inc. (2008), WO2011/025546, and the like].

Manufacturing Method 17

Among compounds (II), compound (II-E) wherein X is —CH(OH)— or —CH═CH—can be manufactured according to the following steps:

[wherein A, A^(B), A^(C), R², X⁷, M¹ and n2 are the same as thedefinition described above; and X^(C) represents —CH(OH)— or —CH═CH—].Step 72

Compound (XII-f) wherein X^(C) is —CH(OH)— can be manufactured byreacting compound (XII-e) in a solvent with compound (a-16) preferablyin 1 to 10 equivalent amount, for 5 minutes to 72 hours at a temperaturebetween −78° C. and the boiling point of the solvent used.

Compound (XII-e) can be obtained as a commercially available product oralso manufactured by methods equivalent to a method described inwell-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume1-64, John Wiley & Sons Inc. (2008), and the like].

Compound (a-16) can be obtained as a commercially available product orby well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesisof organic compounds VI, Organic synthesis using metal” p. 59, Maruzen(2005)] or its equivalent methods.

The solvents include, for example, toluene, diethyl ether, THF, DME,1,4-dioxane, and hexane and the like. They are used alone or inmixtures.

Step 73

Compound (XII-f) wherein X^(C) is —CH═CH— can be manufactured byreacting compound (XII-e) in a solvent with compound (a-17) preferablyin 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presenceof a base preferably in 0.1 to 10 equivalent amount at a temperaturebetween −78° C. and the boiling point of the solvent used.

The bases include, for example, potassium acetate, sodium bicarbonate,potassium carbonate, potassium hydroxide, sodium hydroxide, sodiummethoxide, potassium tert-butoxide, triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and thelike.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP. They are usedalone or in mixtures.

Compound (a-17) can be obtained as a commercially available product, orby well-known methods [e.g., “Jikken Kagaku Koza 24, 4th Ed.” p. 252,Maruzen (2000)] or its equivalent methods.

Step 74

When compound (XII-f) wherein X⁷ is bonded to the sp³ carbonconstituting A is used, compound (XII-g) can be manufactured by reactingcompound (XII-f) in a solvent with a cyanating agent preferably in 1 to10 equivalent amount, for 5 minutes to 72 hours in the presence of, ifneeded, a base preferably in 1 to 10 equivalent amount at a temperaturebetween −20° C. and 150° C.

The cyanating agents include, for example, sodium cyanide, potassiumcyanide, tetrabutylammonium cyanide, and trimethylsilyl cyanide and thelike.

The bases include, for example, potassium carbonate, potassiumhydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide,triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, andDBU and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are usedalone or in mixtures.

Step 75

When compound (XII-f) wherein X⁷ is bonded to the sp² carbonconstituting A is used, compound (XII-g) can be manufactured by reactingcompound (XII-f) in a solvent with a cyanating agent preferably in 1equivalent to 10 equivalent amount for 5 minutes to 72 hours, in thepresence of a base preferably in 0.1 to 10 equivalent amount and apalladium catalyst preferably in 0.001 to 0.5 equivalent amount at atemperature between −20° C. and the boiling point of the solvent used,or if needed, using a microwave reaction device and at a temperaturebetween 0° C. and 200° C.

The cyanating agents include, for example, zinc cyanide, sodium cyanide,and potassium cyanide and the like.

The bases include, for example, sodium carbonate, potassium carbonate,potassium phosphate, potassium hydroxide, sodium hydroxide, potassiumtert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, and DBU and the like.

The palladium catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium, and1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, and water and the like. They are used alone or in mixtures.

Step 75-2

Compound (II-E) can be manufactured by a method similar to step 12 ofmanufacturing method 1 using compound (XII-g).

Manufacturing Method 18

Among compounds (II), compounds (II-F), (II-G) and (II-H) wherein X is—CHR^(X2)— (wherein R^(X2) represents hydrogen atom or hydroxy) or —CO—can be manufactured according to the following steps:

(wherein A, R² and n2 are the same as the definition described above).Step 76

Compound (II-F) can be manufactured by a method similar to step 12 ofmanufacturing method 1 using compound (XII-g-1).

Compound (XII-g-1) can be obtained according to step 72 of manufacturingmethod 17.

Step 77

Compound (XII-h) can be manufactured by treating compound (XII-g-1) in asolvent or without solvent with a chlorinating agent preferably in 1 toa large excess amount, in the presence of, if needed, an additivepreferably in the equal amount of a catalyst to 1 equivalent amount at atemperature between −20° C. and 150° C. for 5 minutes to 72 hours.

The chlorinating agents include, for example, phosphorus oxychloride,phosphorus pentachioride, phosphorus trichloride, and thionyl chlorideand the like.

The additives include, for example, DMF, pyridine, anddiisopropylethylamine and the like.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, diethyl ether, THF, DME, 1,4-dioxane, DMF,DMA, NMP, and pyridine and the like. They are used alone or in mixtures.

Step 78

Compound (II-G) can be manufactured by a method similar to step 12 ofmanufacturing method 1 using compound (XII-h).

Step 79

Compound (XII-i) can be manufactured by a method similar to step 55 ofmanufacturing method 13 using compound (XII-g-1).

Step 80

Compound (II-H) can be manufactured by a method similar to step 12 ofmanufacturing method 1 using compound (XII-i).

Manufacturing Method 19

Among compounds (II), compound (II-J) wherein n is 1 and X is —CH₂— canbe manufactured according to the following step:

(wherein A and R² are the same as the definition described above).Step 81

Compound (II-J) can be manufactured by a method similar to step 12 usingcompound (XII-g-2).

Compound (XII-g-2) can be obtained according to the method of step 73 ofmanufacturing method 17.

Manufacturing Method 20

Among compounds (I), compound (I-b) wherein X is —SO₂— can also bemanufactured according to the following step:

(wherein R¹, R², n1, n2 and A are each the same as the definitiondescribed above, and the wavy line part between R¹ and the adjacentcarbon atom indicates cis or trans configuration).

Compound (I-a) can be obtained according to the method of step 42 ofmanufacturing method 10.

Step 82

Compound (I-b) can be manufactured by a method similar to step 62 usingcompound (I-a).

Manufacturing Method 21

Among compounds (II), compound (II-K) and compound (II-M) as abenzoxazole derivative or a benzothiazole derivative can be manufacturedaccording to the following steps:

(wherein R², R^(2A), R⁵, R⁶, X¹, X², X³, and n2 are the same as thedefinition described above; and X⁸ represents —O— or —S—).Step 83

Compound (XIII-b) can be manufactured using compound (XIII-a), forexample, by methods equivalent to a method described in “Jikken KagakuKoza 13, 5th Ed., Synthesis of organic compounds I, hydrogen/halogencompounds”, Maruzen (2005) and the like.

For example, compound (XIII-b) can be manufactured by reacting compound(XIII-a) in a solvent with 1 equivalent to a large excess amount of ahalogenating agent for 5 minutes to 72 hours at a temperature between−78° C. and the boiling point of the solvent used.

Compound (XIII-a) can be obtained as a commercially available product orby well-known methods (e.g., Japanese Unexamined Patent ApplicationPublication No. 2009-40711 and the like) or their equivalent methods.

The halogenating agents include, for example, chlorine, bromine, iodine,N,N,N,N-tetra-n-butylammonium tribromide, N-chlorosuccinimide,N-bromosuccinimide, N-iodosuccinimide, and the like.

The solvents include, for example, acetone, 1,4-dioxane, acetonitrile,chloroform, dichloromethane, THF, DME, ethyl acetate, methanol, ethanol,DMF, acetic acid, water, and the like. They are used alone or inmixtures.

Step 84

Compound (XIII-c) can be manufactured by a method similar to step 18using compound (XIII-b).

Step 85

Compound (XIII-d) wherein n2 is 1 can be manufactured using compounds(XIII-c) and (a-6) or compounds (XIII-c) and (a-7) by a method similarto step 13.

Step 86

Compound (XIII-d) wherein n2 is 0 can be manufactured using compounds(XIII-c) and (a-4) by a method similar to step 3.

Furthermore, as an alternative method, compound (XIII-d), wherein n2 is0 and R² is optionally substituted aryl or optionally substitutedaromatic heterocyclic group, can be manufactured using compounds(XIII-c) and (a-3) by a method similar to step 2.

Step 87

Compound (II-K) can be manufactured by reacting compound (XIII-d) in asolvent with an ammonia source preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours in the presence of a metallic catalystpreferably in 0.01 to 1 equivalent amount, and if needed, a basepreferably in 1 equivalent to a large excess amount, and if needed, aligand preferably in 0.01 to 1 equivalent amount, at a temperaturebetween 0° C. and the boiling point of the solvent used.

The metallic catalysts include, for example, copper(0) copper(I) iodide,copper(II) acetate, copper(II) oxide, copper(I) chloride, copper(II)sulfate, palladium acetate, tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct and the like.

The bases include, for example, potassium carbonate, cesium carbonate,lithium chloride, potassium chloride, potassium tert-butoxide, sodiumtert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodiumcarbonate, sodium hydroxide, potassium phosphate, ethylenediamine,glycine, N-methylpyrrolidine, pyridine, 1,2-diaminocyclohexane and thelike.

The ligands include, for example, phenanthroline, trans-1,2-cyclohexanediamine, picolinic acid, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,o-tolylphosphine, tributylphosphine, di-tert-butydiphenylphosphine,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyland the like. Ligands are preferably used when palladium catalysts suchas palladium acetate, tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene dichloropalladiu dichloromethane1:1 adduct, and the like are used as metalic catalysts.

The ammonia sources include, for example, ammoniacal water, ammoniumformate, ammonium acetate and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, DMF, HMPA, DMSO, 1,4-dioxane, water and thelike. They are used alone or in mixtures.

Step 88

Compound (X III-e) can be manufactured by treating compound (XIII-d) ina solvent with a cyano source preferably in 1 to 10 equivalent amountfor 1 minute to 72 hours, if needed, in the presence of a palladiumcatalyst preferably in 0.01 to 1 equivalent amount, at a temperaturebetween 0° C. and the boiling point of the solvent used (between 0° C.and 200° C. when a microwave reaction device is used).

The cyano sources include, for example, zinc(II) cyanide, copper(I)cyanide and the like.

The palladium catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene dichloropalladiumidichloromethane1:1 adduct and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, water and the like. They are used alone or in mixtures.

Step 89

Compound (II-M) can be manufactured by a method similar to step 12 usingcompound (XIII-e).

Manufacturing Method 22

Among compounds (II), compound (II-N) or compound (II-O) as abenzoxazole derivative or a benzothiazole derivative can be manufacturedaccording to the following steps:

(wherein R², R^(2A), R⁵, R⁶, X¹, X², X⁸, and n2 are the same as thedefinition described above).Step 90

Compound (XIII-g) can be manufactured by a method similar to step 83using compound (XIII-f).

Compound (XIII-f) can be obtained as a commercially available product orby well-known methods (e.g., Japanese Unexamined Patent ApplicationPublication No, 2009-40711 and the like) or their equivalent methods.

Step 91

Compound (XIII-h) can be manufactured by a method similar to step 18using compound (XIII-g).

Step 92

Compound (XIII-i) wherein n2 is 1 can be manufactured using compounds(XIII-h) and (a-6) or compounds (XIII-h) and (a-7) by a method similarto step 13.

Step 93

Compound (XIII-i) wherein n2 is 0 can be manufactured using compounds(XIII-h) and (a-4) by a method similar to step 3.

Furthermore, as an alternative method, compound (XIII-i), wherein n2 is0 and R² is optionally substituted aryl or optionally substitutedaromatic heterocyclic group, can be manufactured using compounds(XIII-h) and (a-3) by a method similar to step 2.

Step 94

Compound (II-N) can be manufactured by a method similar to step 87 usingcompound (XIII-i).

Step 95

Compound (XIII-j) can be manufactured using compound (XIII-i) by amethod similar to step 88.

Step 96

Compound (II-O) can be manufactured by a method similar to step 12 usingcompound (XIII-j).

Manufacturing Method 23

Among compounds (II), compound (II-P) or compound (II-Q) as abenzoxazole derivative can be manufactured according to the followingsteps:

(wherein R², R^(2A), X¹, X² and n2 are the same as the definitiondescribed above; and R¹⁵ represents an amino group or chloromethylgroup).Step 97

Compound (II-P) wherein n2 is 1 can be manufactured using compounds(XIII-k) and (a-6) or compounds (XIII-k) and (a-7) by a method similarto step 13.

Compound (XIII-k) can be obtained as a commercially available product.

Step 98

Compound (II-P) wherein n2 is 0 can be manufactured using compounds(XIII-k) and (a-4) by a method similar to step 3.

Furthermore, as an alternative method, compound (II-P), wherein n2 is 0and R² is optionally substituted aryl or optionally substituted aromaticheterocyclic group, can be manufactured using compounds (XIII-k) and(a-3) by a method similar to step 2.

Step 99

Compound (XIII-m) can be manufactured by reacting compound (II-P),wherein R¹⁵ is chloromethyl, in a solvent with potassium phthalimide in1 to 20 equivalent amount, for 5 minutes to 72 hours in the presence ofa base preferably in 1 to 20 equivalent amount, at a temperature between−78° C. and the boiling point of the solvent used.

The bases include, for example, potassium carbonate, potassium hydroxideand the like.

The solvents include, for example, methanol, ethanol, propanol, THF,1,4-dioxane, DME, toluene, dichloromethane, DMF, water, and the like.They are used alone or in mixtures.

Step 100

Compound (II-Q) can be manufactured by reacting compound (XIII-m) in asolvent in the presence of a base in 1 equivalent to a large excessamount for 5 minutes to 72 hours at a temperature between 0° C. and theboiling point of the solvent used.

The bases include, for example, sodium hydroxide, potassium hydroxide,lithium hydroxide, hydrazine monohydrate and the like.

The solvents include, for example, water-containing solvents. Saidsolvents are, for example, methanol, ethanol, propanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and thelike. They are used by mixing with water, or mixing each solvent andfurther adding water thereto.

Manufacturing Method 24

Among compounds (II) including 2,3-dihydrobenzofuran derivative,2,3-dihydrobenzothiophene derivative or 2,3-dihydrobenzothiophene1,1-dioxide derivative, compound (II-R) wherein X is —O—, compound(II-S) wherein X is —NH—CO—, compound (II-T) wherein X is —CH═CH—, and(II-U) wherein X is —CH₂— can be manufactured according to the followingsteps:

(wherein R², R^(2A), X¹, X², X³, and n2 are the same as the definitiondescribed above; R¹⁶ represents a hydrogen atom or substituents except ahalogen atom which are described above as the substituents for theoptionally substituted heterocyclic diyl; and X⁹ represents —O—, —S— or—SO₂—).Step 101

Compound (XIV-b) can be manufactured by a method similar to step 22using compound (XIV-a).

Compound (XIV-a) can be obtained as a commercially available product orby well-known methods (e.g., WO2010/104194, WO2014/146493 and the like)or their equivalent methods.

Step 102

Compound (XIV-c) can be manufactured by reacting compound (XIV-b) in asolvent or without solvent (i) with a hydrogen source preferably in 2equivalents to a large excess amount for 5 minutes to 72 hours, or (ii)with hydrogen under the hydrogen atmosphere preferably at 1 to 20atmospheric pressure for 5 minutes to 72 hours, by adding, if needed, anacid preferably in 1 equivalent to a large excess amount or if needed,an ammonia-alcoholic solution preferably in 1 equivalent to a largeexcess amount, in the presence of a catalyst preferably in 0.01 to 50%by weight relative to compound (XIV-b), at a temperature between −20° C.and the boiling point of the solvent used (between 0° C. and 150° C.when without solvent).

The acids include, for example, acetic acid, hydrochloric acid and thelike.

The ammonia-alcoholic solutions include, for example, anammonia-methanol solution, an ammonia-ethanol solution, anammonia-2-propanol solution and the like.

The catalysts include, for example, palladium carbon, Raney nickel andthe like.

The hydrogen sources include, for example, formic acid, ammoniumformate, sodium formate, cyclohexadiene, hydrazine and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, water and the like. They are used alone or in mixtures.

Furthermore, as an alternative method, compound (XIV-c) can bemanufactured by reacting compound (XIV-b) in a solvent with a metal ormetal salt preferably in 1 to 10 equivalent amount, by adding, ifneeded, an acid preferably in 1 equivalent to a large excess amount, ata temperature between −20° C. and the boiling point of the solvent usedfor 5 minutes to 72 hours.

The acids include, for example, acetic acid, hydrochloric acid and thelike.

The metals or metal salts include, for example, tin, zinc, iron,samarium, indium, tin dichloride and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA,NMP, water and the like. They are used alone or in mixtures.

Step 103

Compound (XIV-d) can be manufactured by reacting compound (XIV-c) in asolvent with pinacol diborane preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to10 equivalent amount and a palladium catalyst preferably in 0.001 to 0.5equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

The bases include, for example, potassium acetate, sodium acetate,potassium carbonate, potassium phosphate and the like.

The palladium catalysts include, for example, palladium acetate,tris(dibenzylidene acetone)dipalladium,tetrakis(triphenylphosphine)palladium,1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane1:1 adduct and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like.They are used alone or in mixtures.

Step 104

Compound (XIV-e) can be manufactured by reacting compound (XIV-d) in asolvent with an oxidizing agent preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours at a temperature between −20° C. and theboiling point of the solvent used.

The oxidizing agents include, for example, hydrogen peroxide, ureahydrogen peroxide adduct and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like.They are used alone or in mixtures.

Step 105

Compound (II-R) wherein n2 is 1 can be manufactured using compounds(XIV-e) and (a-6), or compounds (XIV-e) and (a-7) by a method similar tostep 13.

Step 106

Compound (II-R) wherein n2 is 0 can be manufactured using compounds(XIV-e) and (a-4) by a method similar to step 3.

Furthermore, as an alternative method, compound (II-R), wherein n2 is 0and R² is optionally substituted aryl or optionally substituted aromaticheterocyclic group, can be manufactured using compounds (XIV-e) and(a-3) by a method similar to step 2.

Step 107

Compound (II-S) can be manufactured using compounds (XIV-c) and (a-14)by a method similar to step 65.

Step 108

Compound (II-T) can be manufactured using compounds (XIV-c) and (a-15)by a method similar to step 66.

Step 109

Compound (II-U) can be manufactured using compound (II-T) by a methodsimilar to step 17.

Manufacturing Method 25

Among compounds (II), compound (II-V) as a 2,3-dihydrobenzofuranderivative having a halogen atom as a substituent,2,3-dihydrobenzothiophene derivative having a halogen atom as asubstituent or 2,3-dihydrobenzothiophene 1,1-dioxide derivative having ahalogen atom as a substituent, can be manufactured according to thefollowing steps:

(wherein R², R^(2A), X¹, X², X⁹ and n2 are the same as the definitiondescribed above; and R¹⁷ represents fluorine atom, chlorine atom,bromine atom or iodine atom).Step 110

Compound (XVI-g) can be manufactured by a method similar to step 101using compound (XIV-f).

Compound (XIV-f) can be obtained as a commercially available product orby well-known methods (e.g., WO2014/146493 and the like) or theirequivalent methods.

Step 111

Compound (XVI-h) can be manufactured by a method similar to step 102using compound (XIV-g).

Step 112

Compound (II-V) wherein n2 is 1 can be manufactured using compounds(XIV-h) and (a-6) or compounds (XIV-h) and (a-7) by a method similar tostep 13.

Step 113

Compound (II-V) wherein n2 is 0 can be manufactured using compounds(XIV-h) and (a-4) by a method similar to step 3.

Furthermore, as an alternative method, compound (II-V), wherein n2 is 0and R² is optionally substituted aryl or optionally substituted aromaticheterocyclic group, can be manufactured using compounds (XIV-h) and(a-3) by a method similar to step 2.

Manufacturing Method 26

Among compounds (II), compounds (II-W) and (II-X), that are eachdihydropyranopyridine derivative, can be manufactured according to thefollowing steps:

(wherein R², X^(A), X^(B) and n2 are the same as the definitiondescribed above; and R¹⁰ represents chlorine atom or bromine atom; X^(D)represents —SO₂— or —CH₂CH₂—).Step 114

Compound (XV-b) wherein X^(B) is X^(A) can be manufactured by a methodsimilar to step 34 using compounds (XV-a) and (a-6a).

Compound (XV-a) can be obtained as a commercially available product.

Step 115

Compound (XV-b) wherein X^(B) is —NH—CO— can be manufactured usingcompounds (XV-a) and (a-14) by a method similar to step 65.

Step 116

Compound (XV-b) wherein X⁵ is —CH═CH— can be manufactured usingcompounds (XV-a) and (a-15) by a method similar to step 66.

Step 117

Compound (II-W) can be manufactured by a method similar to step 1 usingcompound (XV-b).

Step 118

Compound (XV-c) can be manufactured by a method similar to step 17 usingcompound (XV-b) wherein X^(B) is —CH═CH—.

Step 119

Compound (II-X) wherein X^(D) is —CH₂CH₂— can be manufactured usingcompound (XV-c) by a method similar to step 1.

Step 120

Compound (11-X) wherein X^(D) is —SO₂— can be manufactured by a methodsimilar to step 62 using compound (II-W) wherein X^(B) is —S—.

Manufacturing Method 27

Among compounds (II), compound (II-Y) and compound (II-Z) that are eachbenzoxazepine derivative can be manufactured according to the followingsteps:

(wherein R², R^(2A), R⁶, X¹, X², X⁵ and n2 are the same as thedefinition described above; and R¹⁸ represents optionally substitutedalkyl).Step 121

Compound (XVI-b) can be manufactured by reacting compound (XVI-a) in asolvent with compound (a-18) preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours in the presence of a reducing agent preferablyin 1 to 10 equivalent amount, an acid preferably in 1 to 10 equivalentamount, and if needed, a metallic catalyst preferably in 0.01 to 1equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

Compound (XVI-a) can be obtained as a commercially available product.

Compound (a-18) can be obtained as a commercially available product, orobtained by well-known methods [e.g., “Jikken Kagaku Koza 14, 5th Ed.,Synthesis of organic compounds II, alcohol/amine”, Maruzen (2005)] or byits equivalent methods.

The reducing agents include, for example, sodium triacetoxyborohydride,sodium cyanoborohydride and the like.

The acids include, for example, hydrochloric acid, sulfuric acid, formicacid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and thelike.

The metallic catalysts include, for example,dichloro(pentamethylcyclopentadienyl)rhodium(III),chloro[N-{4-(dimethylamino)phenyl}-2-pyridinecarboxyamidate](pentamethylcyclopentadienyl)iridium(III) and the like.

The solvents include, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like.They are used alone or in mixtures.

Step 122

Compound (XVI-c) can be manufactured by reacting compound (XVI-b) in asolvent for 5 minutes to 72 hours in the presence of a phosphinecompound preferably in 1 to 10 equivalent amount and an azo compoundpreferably in 1 to 10 equivalent amount, at a temperature between −78°C. and the boiling point of the solvent used.

The phosphine compounds include, for example, triphenylphosphine,tributylphosphine and the like.

The azo compounds include, for example, DEAD, di-tert-butylazadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethylazadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine,N,N,N′,N′-tetraisopropyl azadicarboxamide and the like.

The solvents include, for example, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP and the like. Theyare used alone or in mixtures.

Step 123

Compound (XVI-d) can be manufactured using compound (XVI-c) by a methodsimilar to step 18.

Step 124

Compound (XVI-e) wherein n2 is 1 can be manufactured using compounds(XVI-d) and (a-6) or compounds (XVI-d) and (a-7) by a method similar tostep 13.

Step 125

Compound XVI-e wherein n2 is 0 can be manufactured using compounds(XVI-d) and (a-4) by a method similar to step 3.

Furthermore, as an alternative method, compound (XVI-e), wherein n2 is 0and R² is optionally substituted aryl or optionally substituted aromaticheterocyclic group, can be manufactured using compounds (XVI-d) and(a-3) by a method similar to step 2.

Step 126

Compound (XVI-f) can be manufactured using compound (XVI-e) by a methodsimilar to step 88.

Step 127

Compound (II-Y) can be manufactured using compound (XVI-e) by a methodsimilar to step 87.

Step 128

Compound (II-Z) can be manufactured by a method similar to step 12 usingcompound (XVI-f).

Manufacturing Method 28

Among compounds (II), compound (II-Aa) that is a tetrahydrobenzoxepinderivative can be manufactured according to the following steps:

(wherein R², R^(2A), X¹, X² and n2 are the same as the definitiondescribed above).Step 129

Compound (XVII-b) wherein n2 is 1 can be manufactured using compounds(XVII-a) and (a-6) or compounds (XVII-a) and (a-7) by a method similarto step 13.

Compound (XVII-a) can be obtained as a commercially available product.

Step 130

Compound (XVII-b) wherein n2 is 0 can be manufactured using compounds(XVII-a) and (a-3) by a method similar to step 2.

Step 131

Compound (XVII-c) can be manufactured by reacting compound (XVII-b) in asolvent with compound (a-19) preferably in 1 to 10 equivalent amount,for 5 minutes to 72 hours in the presence of a base preferably in 1 to10 equivalent amount, at a temperature between −20° C. and the boilingpoint of the solvent used.

Compound (a-19) can be obtained as a commercially available product.

The bases include, for example, sodium carbonate, potassium carbonate,potassium hydroxide, sodium hydroxide, potassium tert-butoxide,diisopropyle hylamine, DBU and the like.

The solvents include, for example, methanol, ethanol, toluene, ethylacetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, waterand the like. They are used alone or in mixtures.

Step 132

Compound (XVII-d) can be manufactured by treating compound (XVII-c) in asolvent in the presence of a base preferably in 1 equivalent to a largeexcess amount, for 5 minutes to 72 hours at a temperature between 0° C.and the boiling point of the solvent used.

The bases include, for example, potassium carbonate, lithium hydroxide,potassium hydroxide, sodium hydroxide, sodium methoxide and the like.

The solvents include, for example, water-containing solvents. Saidsolvents are, for example, methanol, ethanol, dichloromethane,chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile,diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and thelike. They are used by mixing with water, or mixing each solvent andfurther adding water thereto.

Step 133

Compound (XVII-e) can be manufactured by reacting compound (XVII-d) in asolvent or without solvent in the presence of an acid preferably in 1equivalent to a large excess amount and if needed, a chlorinating agentin 1 equivalent to a large excess amount, at a temperature between 0° C.and the boiling point of the solvent used (between 0° C. and 150° C.when without solvent) for 5 minutes to 72 hours.

The acids include, for example, hydrochloric acid, sulfuric acid,trifluoroacetic acid and the like.

The chlorinating agents include, for example, thionyl chloride,phosphorus oxychloride, oxalyl chloride, phosphorus pentoxide and thelike.

The solvents include, for example, dichloromethane, chloroform,1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether,THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and the like. They areused alone or in mixtures.

Step 134

Compound (II-Aa) can be manufactured using compound (XVII-e) by a methodsimilar to step 1.

Conversion of functional groups contained in R¹ or R² of compound (I)can be conducted by well-known methods [methods described inComprehensive Organic Transformations 2nd Ed., by R. C. Larock, VchVerlagsgesellschaft Mbh (1999), and the like] or their equivalentmethods.

The intermediate and the target compound in each manufacturing methodmentioned above can be isolated and purified by anisolation/purification procedure commonly used in synthetic organicchemistry, for example, by subjecting to filtration, extraction,washing, drying, concentration, recrystallization, and variouschromatography and the like. Furthermore, the intermediates can besupplied to the next reactions without being particularly purified.

Among compounds (I), stereoisomers such as geometric isomer, opticalisomer, and the like, and tautomer and the like can be present, but thepresent invention includes all possible isomers and mixtures thereof.

A part or all of each atom in compound (I) may be substituted with thecorresponding isotope, and the present invention includes thesecompounds substituted with these isotopes. For example, a part or all ofhydrogen atom(s) in compound (I) may be hydrogen atom having an atomicweight of 2 (deuterium atom).

Compound (I), wherein a part or all of each atom is substituted with thecorresponding isotope, can be manufactured by a method similar to themanufacturing method mentioned above using commercially availablebuilding blocks. Furthermore, a compound wherein a part or all of eachhydrogen atom in compound (I) is substituted with deuterium can besynthesized by, for example, 1) a method by which carboxylic acid andthe like are deuterated under the basic conditions using deuteriumperoxide (refer to U.S. Pat. No. 3,849,458), 2) a method by whichalcohol, carboxylic acid and the like are deuterated using an iridiumcomplex as a catalyst and heavy water as a deuterium source [refer to J.Am. Chem. Soc., Vol. 124, No. 10, 2092 (2002)], 3) a method by whichaliphatic acid is deuterated using palladium carbon as a catalyst andonly deuterium gas as a deuterium source [refer to LIPIDS, Vol. 9, No.11, 913 (1974)], 4) a method by which acrylic acid, methyl acrylate,methacrylic acid, methyl methacrylate, and the like are deuterated usinga metal such as platinum, palladium, rhodium, ruthenium, iridium, andthe like as a catalyst, and using heavy water or heavy water anddeuterium gas as a deuterium source (refer to Japanese Examined PatentApplication 5-19536, Japanese Unexamined Patent Application PublicationNo. 61-277648 and Japanese Unexamined Patent Application Publication No.61-275241), 5) a method by which acrylic acid, methyl methacrylate, andthe like are deuterated using a catalyst such as palladium, nickel,copper or copper chromite, and the like, and heavy water as a deuteriumsource (refer to Japanese Unexamined Patent Application Publication No.63-198638), and the like.

When a salt of compound (I) is desired, in the case where compound (I)is obtained in the form of a salt, it can be purified as it is, or inthe case where it is obtained in a free form, compound (I) can bedissolved or suspended in a suitable solvent and an acid or a base maybe added to form a salt thereof followed by isolation and purification.

Furthermore, compound (I) and a pharmaceutically acceptable salt thereofmay be present in the form of an adduct with water or various solvents,but these adducts are also included in the present invention.

Compounds represented in formula (I) of the present invention (compounds(I)) are preferably compounds described in the following Tables 1 to 32.

TABLE 1

Compound No. R² 1

2

3

4

5

6

7

8

9

10

11

12 Compound with retention time of 4.17 minutes among two enantiomerscontained in compound 3 13 Compound with retention time of 3.31 minutesamong two enantiomers contained in compound 3 14

15

16

TABLE 2 Compound No. 17

18

19

20

21

22

23

24

25

26

TABLE 3

Compound No. R¹ R⁵ R² 27 H Me

28 H Me

29 CF₃ Me

30 H F

31 H F

32 H OMe

33 H OMe

TABLE 4 Compound No. 34

35

36

37

38

39

40

41

TABLE 5

Compound No. R² 42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

TABLE 6 Compound No. 59 Compound with retention time of 3.48 minutesamong two enantiomers contained in compound 42 60 Compound withretention time of 4.57 minutes among two enantiomers contained incompound 42 61 Compound with retention time of 4.17 minutes among twoenantiomers contained in compound 44 62 Compound with retention time of5.74 minutes among two enantiomers contained in compound 44 63 Compoundwith retention time of 5.95 minutes among two enantiomers contained incompound 50 64 Compound with retention time of 7.82 minutes among twoenantiomers contained in compound 50 65 Compound with retention time of6.65 minutes among two enantiomers contained in compound 35 66 Compoundwith retention time of 8.25 minutes among two enantiomers contained incompound 35

TABLE 7

Compound No. R¹⁰ R² 67 H

68 H

69 H

70 Cl

71 OMe

72

73

74

75 Cl

76 Cl

77 Cl

78

TABLE 8

Compound No R¹⁰ R² 79 H

80. H

81 OMe

82 Cl

TABLE 9

Compound No. R1 A 83 H

84 H

85 H

86 H

87 H

88 H

89 H

90 Me

91 H

92 H

93 H

TABLE 10

Compound No. R² 94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

TABLE 11

Compound No. R¹⁵ R² 111 H

112 Me

113 H

114 H

115 Me

116 H

117 Me

118 H

119 H

120 H

121 H

122 H

TABLE 12

Compound No. R² 123

124

125

126

127

128

129

130

131

132

TABLE 13

Compound No. R¹ R¹⁵ R² 133 H H

134 H H

135 CF₃ H

136 H H

137 H H

138 H H

139 H Cl

140 H H

141 H H

142 H H

143 H H

TABLE 14

Compound No. R¹ R² 144 H

145 CF₃

146 H

147 CF₃

148 H

149 H

150 H

151 H

TABLE 15

Substitution Position of Compound No. acrylamide n1 R² R⁵ 152 4 1

H 153 3 0

Br 154 3 0

H 155 3 0

H 156 3 0

H 157 3 0

H 158 3 0

H 159 3 0

H 160 3 0

H 161 3 0

H 162 3 0

CF₃

TABLE 16

Compound No. R² R⁵ 163

OMe 164

OMe 165

OMe 166

F 167

F 168

Cl 169

Br 170

OH 171

F 172

OEt 173

NMe₂

TABLE 17 Compound No. 174

175

176

177

TABLE 18

Compound No. R² R¹⁰ 178

Cl 179

OMe 180

181

Cl 182

CN 183

Me 184

Me 185

186

Et 187

Cl 188

OEt 189

Cl

TABLE 19 Compound No. 190

191

TABLE 20

Compound No. R² 192

193

194

TABLE 21

Compound No. R² Rx Ry X 195

H H

196

H H

197

H H

198

H H

199

H Me

200

H Me

201

Me H

202

H H

203

H H

204

H H

TABLE 22

Compound No. Rz X n2 205 H

0 206 H

0 207 H

0 208 H

0 209 H

1 210 H

0 211 H

0 212 Me

0 213 OH

0

TABLE 23 Compound No. 214

215

216

217

218

219

220

221

TABLE 24 Compound No. 222

223

224

225

TABLE 25 Compound No. 226

227

228

TABLE 26 Compound No. 229 Compound with retention time of 2.61 minutesamong two enantiomers contained in compound 51 230 Compound withretention time of 3.28 minutes among two enantiomers contained incompound 51 231 Compound with retention time of 2.44 minutes among twoenantiomers contained in compound 153 232 Compound with retention timeof 3.24 minutes among two enantiomers contained in compound 153 233Compound with retention time of 4.56 minutes among two enantiomerscontained in compound 40 234 Compound with retention time of 5.07minutes among two enantiomers contained in compound 40 235 Compound withretention time of 3.67 minutes among two enantiomers contained incompound 41 236 Compound with retention time of 4.35 minutes among twoenantiomers contained in compound 41 237 Compound with retention time of5.14 minutes among two enantiomers contained in compound 33 238 Compoundwith retention time of 6.79 minutes among two enantiomers contained incompound 33 239 Compound with retention time of 6.19 minutes among twoenantiomers contained in compound 31 240 Compound with retention time of7.43 minutes among two enantiomers contained in compound 31 241 Compoundwith retention time of 2.73 minutes among two enantiomers contained incompound 76 242 Compound with retention time of 3.41 minutes among twoenantiomers contained in compound 76

TABLE 27

Compound No. —R⁵ —R² 243

244

245

246

247

248

249

250

251

252

TABLE 28 Compound No. 253

254

255

256

257

258

259

TABLE 29 Compound No. 260

261

262

263

264

265

266

TABLE 30

Compound No. —X— n2 267

1 268

0 269

0 270

0 271

0 272

0

TABLE 31

Compound No. n2 —R² 275 0

276 0

277 0

278 0

279 0

280 0

281 0

282 1

TABLE 32 Compound No. 283

284

285

286

287

288

Compound (I) or a pharmaceutically acceptable salt thereof can beadministered alone, but generally it is desirable to provide it asvarious pharmaceutical preparations. In addition, these pharmaceuticalpreparations are used for animals or humans, preferably humans.

The pharmaceutical preparation related to the present invention cancontain compound (I) or a pharmaceutically acceptable salt thereof as anactive ingredient by itself, or as a mixture with any other activeingredients used for the treatment. Furthermore, those pharmaceuticalpreparations are manufactured by a well-known method in the technicalfield of pharmaceutics by mixing the active ingredient with one kind ormore pharmaceutically acceptable carriers (e.g., an attenuant, asolvent, a diluent and the like).

The most effective administration route is desirably used for thetreatment. For example, it includes an oral or parental administrationroute such as intravenous injection and the like.

Administration forms include, for example, tablets, injection and thelike.

Suitable formulation for the oral administration, for example, such astablets, can be manufactured using a diluent such as lactose, adisintegrant such as starch, a lubricant such as magnesium stearate, abinder such as hydroxypropylcellulose, and the like.

Suitable formulation for the parenteral administration, for example,such as injection, can be manufactured using an attenuant such as a saltsolution, glucose solution or mixed solution of saline and glucosesolutions; a solvent or the like.

Dose and frequency of administration of compound (I) or apharmaceutically acceptable salt thereof differ depending onadministration form, age, body weight, the nature of the symptoms to betreated or severity of them or the like of the patient. Generally, theyare administered for oral administration at a dosage of 0.01 to 1000 mgper adult, preferably at a dosage of 0.05 to 100 mg once daily orseveral times a day. In the case of parenteral administrations such asintravenous administration, they are administered at a dosage of 0.001to 1000 mg per adult, preferably at a dosage of 0.01 to 100 mg oncedaily or several times a day. However, the dose and frequency of theadministration vary depending on the above-mentioned conditions.

According to another embodiment of the present invention, provided is apharmaceutical composition comprising compound (I) or a pharmaceuticallyacceptable salt thereof and a carrier. The pharmaceutical composition ofthe present invention is used in administration routes and dosage formsand the like similar to the pharmaceutical preparation mentioned above.Furthermore, the carrier contained in the pharmaceutical composition ofthe present invention may be an attenuant, solvent, diluent, and thelike that are similar to the case of the pharmaceutical preparationmentioned above. Furthermore, the pharmaceutical composition of thepresent invention is used preferably for the treatment or prevention ofcancers, more preferably for the treatment or prevention of one or twoor more cancers selected from the group consisting of mesothelioma, lungcancer, ovarian cancer and liver cancer. Here, prevention means that theclinical condition of a disease, the outcome of biological symptoms orthe severity of the disease is substantially reduced, or thatdevelopment of such condition or the biological symptoms is delayed, andthe like. The situation is similar to the following prevention.

According to another embodiment of the present invention, provided is amethod for the treatment or prevention comprising administering compound(I) of the present invention or a pharmaceutically acceptable saltthereof to a subject (preferably a subject in need thereof). The subjectincludes, for example, an animal other than a human, but is preferably ahuman. This is also the same in the following subjects. The method forthe treatment or prevention in the present invention is preferably usedfor the treatment or prevention of cancers, more preferably is used forthe treatment or prevention of one or two or more cancers selected fromthe group consisting of mesothelioma, lung cancer, ovarian cancer andliver cancer.

According to another embodiment, provided is compound (I) of the presentinvention or a pharmaceutically acceptable salt thereof for use as amedicament.

According to another embodiment, provided is compound (I) of the presentinvention or a pharmaceutically acceptable salt thereof for use oftreating or preventing cancers. Here, cancers are preferably one or twoor more cancers selected from the group consisting of mesothelioma, lungcancer, ovarian cancer and liver cancer.

According to another embodiment, provided is use of compound (I) of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of drugs for the treatment or prevention of cancers. Here,cancers are preferably one or two or more cancers selected from thegroup consisting of mesothelioma, lung cancer, ovarian cancer and livercancer.

According to another embodiment, provided is use of compound (I) of thepresent invention or a pharmaceutically acceptable salt thereof for thetreatment or prevention of cancers.

According to another embodiment, provided is a medicament comprisingcompound (I) of the present invention or a pharmaceutically acceptablesalt thereof as an active ingredient.

According to another embodiment, provided is a preventive or therapeuticagent for cancers comprising compound (I) of the present invention or apharmaceutically acceptable salt thereof as an active ingredient.

EXAMPLES

The present invention will be explained by examples more specificallybelow, but the scope of the present invention is not limited to theseexamples.

The pharmacological action of the typical compound (I) will bespecifically explained by a test example.

Test Example 1 Cell Growth Inhibitory Effect on Human Mesothelioma,Human Liver Cancer, Human Ovarian Cancer, and Human Liver Cancer CellLines

NCI-H226 cells, a human mesothelioma cell line (ATCC, CRL-5826),NCI-H322 cells, a human lung cancer cell line (the European Collectionof Authenticated Cell Cultures, 95111734), OUTOKO cells, a human ovariancancer cell line (JCRB cell bank, KRB1048) and HuH28, a human livercancer cell line (JCRB cell bank, KRB0426) were each subcultured bykeeping the cell density under 80% in a RPMI1640 culture medium with 10%fetal bovine serum (FBS). NCI-H226 cells, NCI-H322 cells and SSP-25cells were each suspended in the RPMI1640 culture medium mentionedabove, and plated to a 96-well flat-bottom plate at 500 cells/well ineach well, and incubated at 37° C. in an incubator with 5% CO₂ for oneday. After the incubation, the evaluation of cell growth inhibitoryactivity was started. OVTOKO cells were suspended in the RPMI1640culture medium mentioned above, and plated to a 96-well flat-bottomplate at 250 cells/well in each well, and incubated it at 37° C. in anincubator with 5% CO₂ for one day. After the incubation, the evaluationof the cell growth inhibitory activity was started. The next day, a testcompound was serially diluted to 5 times of its final concentration inthe RPM11640 culture medium mentioned above, and the diluted solutionwas added to each well. In this case, the final concentration of DMSO ineach well was adjusted to 0.1%. After the test compound was added, cellswere incubated at 37° C. in an incubator with 5% CO₂ for 6 days. At theaddition of the test compound and 6 days after the addition, the cellcounting measurement was performed using a cell counting kit 8 (made byDOJINDO) according to a protocol equivalent to DOJINDO's recommendation.A reagent contained in the kit was added to each plate and and colorreaction was performed for 2 or 3 hours at 37° C. in an incubator with5% CO₂. After the reaction, an absorbance at wavelength of 450 nm wasmeasured using a microplate reader. A growth inhibition rate wascalculated according to the following formula, from which theconcentration of a test compound at which cell growth was inhibited by50% (GI₅₀ value) was determined.

$\begin{matrix}{\mspace{515mu}\left\lbrack {{Mathematical}\mspace{14mu}{formula}\mspace{14mu} 1} \right\rbrack} \\{{{Inhibition}\mspace{14mu}{rate}\mspace{14mu}{of}\mspace{14mu}{growth}\mspace{14mu}(\%)} =} \\{\mspace{45mu}{\frac{\begin{matrix}{{\left( {{Absorbance}\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{without}\mspace{14mu}{addition}\mspace{14mu}{of}\mspace{14mu} a\mspace{14mu}{test}\mspace{14mu}{compound}} \right) -}\;} \\\left( {{Absorbance}\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{with}\mspace{14mu}{addition}\mspace{14mu}{of}\mspace{14mu} a\mspace{14mu}{test}\mspace{14mu}{compound}} \right)\end{matrix}}{\begin{matrix}{{\left( {{Absorbance}\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{without}\mspace{14mu}{addition}\mspace{14mu}{of}\mspace{14mu} a\mspace{14mu}{test}\mspace{14mu}{compound}} \right) -}\;} \\{\left( {{Absorbance}\mspace{14mu}{of}\mspace{14mu}{well}\mspace{14mu}{before}\mspace{14mu}{addition}\mspace{14mu}{of}\mspace{14mu} a\mspace{14mu}{test}\mspace{14mu}{compound}} \right)\;}\end{matrix}} \times 100}}\end{matrix}$

Among compounds described in the following examples, compounds 1, 3, 5,11, 19-22, 27, 28, 30-35, 39-44, 50, 51, 56, 59, 60, 68, 70, 71, 76, 82,95, 96, 100, 107-109, 111, 112, 114, 117, 126, 133, 134, 137-139, 143,149-151, 155, 157, 163, 167, 168, 169, 176, 178, 179, 184, 185, 187,189, 190, 199, 200, 201, 202, 203, 211, 212, 214, 216, 219, 222, 223,224, 225, 226, 227, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238,239, 240, 241, 243-245, 247, 249-253, 256, 257, 262-264, 270, 272, 276,277 and 279-288 exhibited a GI₅₀ value of less than 100 nmol/L andcompounds 14, 16, 23, 24, 26, 29, 49, 67, 81, 92-94, 101-103, 105, 106,110, 116, 120, 123, 135, 136, 142, 144, 146, 147, 153, 156, 159, 162,164, 166, 172, 181, 186, 192, 196, 206, 208, 220, 221, 246, 248, 254,255, 259, 261, 265-269, 273, 275 and 278 exhibited a GI₅₀ value of 100nmol/L to 1 μmol/L against the human mesothelioma cell line, NCI-H226cells.

Among compounds described in the following examples, compounds 5, 21,22, 27, 28, 31-33, 35, 37, 40-42, 44, 50, 51, 59, 61, 64, 68, 70, 71,76, 82, 95, 96, 106-109, 111, 112, 114, 117, 126, 134, 137-139, 143,149-151, 155, 157, 162-164, 168, 169, 176, 179, 184, 185, 187, 189, 190,192, 199-203, 206, 208, 211, 212, 214, 216, 219, 220, 222-230, 241,243-253, 256, 257, 259, 262-266, 268-270, 272, 275 and 277-288 exhibiteda GI₅₀ value of less than 1000 nmol/L against the human lung cancer cellline, NCI-H322 cells.

Among compounds described in the following examples, compounds 5, 21,22, 27, 28, 31-33, 35, 37, 40-42, 44, 51, 59, 61, 68, 70, 71, 76, 82,95, 96, 100, 105-109, 111, 112, 114, 117, 126, 134, 137, 138, 143,149-151, 155, 157, 162-164, 168, 169, 176, 179, 184, 185, 187, 189, 190,192, 199, 200-203, 206, 208, 211, 212, 216, 219, 222-224, 226, 227, 229,230, 241, 243, 244, 247, 249,250, 256, 267-273 and 275-288 exhibited aGI₅₀ value of 3000 nmol/L or less against the human ovarian cancer cellline, OVTOKO cells.

Among compounds described in the following examples, compounds 5, 22,28, 31, 33, 40, 68, 95, 96, 107, 108, 111, 112, 114, 117, 126, 134, 137,138, 139, 143, 149-151, 155, 163, 164, 168, 169, 176, 179, 185, 187,189, 190, 192, 199, 200-203, 206, 208, 211, 212 and 222-227, 243-247,249-253, 256, 257, 268-273 and 275-288 exhibited a GI₅₀ value of lessthan 3000 nmol/L against human liver cancer cell line, HuH28 cells.

As mentioned above, compound (I) of the present invention represented intest compounds exhibited a high growth inhibitory effect on NCI-H226cells as the human mesothelioma cell line, on NCI-H322 cells as thehuman lung cancer cell line, on OVTOKO cells as the human ovarian cancercell line, and on HuH28 cells as the human liver cancer cell line.Therefore, compound (I) of the present invention was found to be usefulas a preventive or therapeutic agent or the like for cancers.

The proton nuclear magnetic resonance spectrum (¹H NMR) used in thefollowing examples is measured at 300 MHz or 400 MHz, and sometimes anexchangable proton may not be clearly observed depending on compoundsand measurement conditions. In addition, commonly used notation is usedas one for the multiplicity of signals, but br expresses an apparentwide signal.

Example 1

Step 1

3-Chloro-1-(2,4-dihydroxyphenyl)propan-1-one (Compound 1-1)

To a mixture of resorcinol (5.00 g, 45.4 mmol) and 3-chloropropionicacid (4.90 g, 45.4 mmol), trifluoromethanesulfonic acid (15 mL) wasadded, and the mixture was stirred at 80° C. for 0.5 hours. A reactionliquid obtained by adding dichloromethane (100 mL) to the mixture leftto cool to room temperature was gradually added to water (100 mL). Theorganic layer was extracted with dichloromethane, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtaincompound 1-1 (6.00 g) as a crude product.

¹H NMR (400 MHz, CDCl₃, δ): 12.48 (s, 1H), 7.62 (d, J=11.6 Hz, 1H),6.43-6.39 (m, 2H), 3.90 (t, J=9.2 Hz, 2H), 3.40 (t, J=9.2 Hz, 2H).

Step 2

7-Hydroxychroman-4-one (Compound 1-2)

To compound 1-1 (6.00 g), a 2 mol/L aqueous sodium hydroxide solution(250 mL) was added at −5° C., and the mixture was stirred at roomtemperature for 2 hours. The mixture was cooled to −5° C., and 2 mol/Lsulfuric acid was added to the mixture to adjust pH to 2. The organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain compound 1-2(3.00 g, 40% over two steps).

¹H NMR (400 MHz, DMSO-d₆, δ): 12.48 (s, 1H), 7.62 (d, J=11.6 Hz, 1H),6.43-6.39 (m, 2H), 3.90 (t, J=9.2 Hz, 2H), 3.40 (t, J=9.2 Hz, 2H).

Step 3

7-Phenoxychroman-4-one (Compound 1-3)

Compound 1-2 (0.50 g, 3.04 mmol) was dissolved in dichloromethane (15mL), and phenylboronic acid (0.74 g, 6.09 mmol), pyridine (1.22 mL, 15.2mmol), and copper(II) acetate (0.82 g, 4.57 mmol) were added to thesolution. The solution was stirred at room temperature for 18 hours.Dichloromethane (30 mL) was added to the mixture, followed by filtrationwith Celite®, and the solid on the Celite was washed withdichloromethane (50 mL). The organic layer in the filtrate was washedwith 2 mol/L hydrochloric acid, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=100/0→70/30) to obtaincompound 1-3 (0.075 g, 10%).

¹H NMR (400 MHz, CDCl₃, δ): 7.87 (d, J=8.8 Hz, 1H), 7.42-7.38 (m, 2H),7.09-7.07 (m, 2H), 6.84-6.82 (m, 1H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.42(d, J=2.4 Hz, 1H), 4.50 (t, J=6.4 Hz, 2H), 2.76 (t, J=6.4 Hz, 2H);

ESIMS m/z: [M+H]⁺241.

Step 4

7-Hydroxychroman-4-amine (Compound 1-4)

Compound 1-3 (0.05 g, 0.21 mmol) was dissolved in methanol (3 mL), andammonium acetate (0.24 g, 3.12 mmol) and sodium cyanoborohydride (0.04g, 0.62 mmol) were added to the solution. The mixture was stirred at 80°C. for 18 hours in a sealed tube. The mixture was left to cool to roomtemperature, and water was added to the mixture. The organic layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain compound 1-4 (0.03 g,60%).

¹H NMR (400 MHz, CDCl₃, δ): 7.39-7.34 (m, 3H), 7.12 (t, J=7.6 Hz, 1H),6.99-6.97 (m, 2H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H),4.26-4.20 (m, 1H), 4.14-4.09 (m, 1H), 3.86 (t, J=5.2 Hz, 1H), 2.01-1.94(m, 1H), 1.75-1.68 (m, 1H).

Step 5

N-(7-phenoxychroman-4-yl)acrylamide (Compound 1)

Compound 1-4 (0.15 g, 0.62 mmol) was dissolved in dichloromethane (5mL), and diisopropylethylamine (0.23 mL, 1.24 mmol) and acryloylchloride (0.075 mL, 0.93 mmol) were added to the solution under coolingat 0° C. The mixture was stirred at 0° C. for 0.5 hours. A saturatedaqueous sodium bicarbonate solution was added to the mixture. Theorganic layer was extracted with dichloromethane, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=90/10→50/50) to obtain compound 1 (0.08 g, 44%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.55 (d, J=8.0 Hz, 1H), 7.41-7.36 (m, 2H),7.16-7.13 (m, 2H), 7.00-6.98 (m, 2H), 6.54 (dd, J=8.4, 2.4 Hz, 1H), 6.38(d, J=2.4 Hz, 1H), 6.26 (dd, J=16.8, 9.6 Hz, 1H), 6.15 (dd, J=16.8, 2.4Hz, 1H), 5.62 (dd, J=10.0, 2.4 Hz, 1H), 5.04 (q, J=5.6 Hz, 1H),4.26-4.13 (m, 2H), 2.10-1.86 (m, 2H)

ESIMS m/z: [M−70]⁺ 225.

The following compounds were synthesized in accordance with thesynthesis method of compound 1.

N-{7-(3-chlorophenoxy)chroman-4-yl}acrylamide (Compound 2)

ESIMS m/z: [M−70]⁺259.

N-{7-(p-tolyloxy)chroman-4-yl}acrylamide (Compound 4)

ESIMS m/z: [M−70]⁺239.

Example 2

Step 1

7-(4-Chlorophenoxy)chroman-4-one (Compound 2-1)

Compound 2-1 (0.26 g, 26%) was obtained in the same manner as step 3 ofexample 1, using compound 1-2.

¹H NMR (300 MHz, CDCl₃, δ): 7.87 (d, J=8.7 Hz, 1H), 7.36 (dd, J=6.9, 2.1Hz, 2H), 7.01 (dd, J=6.9, 2.4 Hz, 2H), 6.62 (dd, J=9.0, 2.4 Hz, 1H),6.42 (d, J=2.1 Hz, 1H), 4.51 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.3 Hz, 2H).

Step 2

7-(4-Chlorophenoxy)chroman-4-amine (Compound 2-2)

Compound 2-2 (0.20 g, 80%) was obtained in the same manner as in step 4of example 1, using compound 2-1 obtained in step 1.

¹H NMR (400 MHz, CDCl₃, δ): 7.28-7.24 (m, 3H), 6.95-6.93 (m, 2H), 6.55(dd, J=8.4, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.30-4.18 (m, 2H),4.04-4.02 (m, 1H), 2.18-2.10 (m, 1H), 1.86-1.79 (m, 1H).

Step 3

N-{7-(4-Chlorophenoxy)chroman-4-yl}acrylamide (Compound 3)

Compound 3 (0.11 g, 55%) was obtained in the same manner as step 5 ofexample 1, using compound 2-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.58 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.8 Hz,2H), 7.16 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.57 (dd, J=8.4,2.4 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 6.29-6.13 (m, 2H), 5.63 (dd,J=10.0, 2.4 Hz, 1H), 5.07-5.02 (m, 1H), 4.26-4.14 (m, 2H), 2.10-1.87 (m,2H);

ESIMS m/z: [M−70]⁺ 259.

Step 4

N-{7-(4-Chlorophenoxy)chroman-4-yl}acrylamide (Compounds 12 and 13)

Compound 3 was optically resolved under the following chiral preparativeconditions to obtain compound 13 (17 mg, 34%) having a retention time of3.31 minutes and compound 12 (15 mg, 31%) having a retention time of4.17 minutes.

-   Compound 12: ESIMS m/z: [M+H]⁺ 330.-   Compound 13: ESIMS m/z: [M+H]⁺ 330.    Chiral Preparative Conditions-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IB/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 90% carbon dioxide/10% methanol-   Preparative time: 6 minutes-   Flow rate: 30 mL/minute-   Retention time: 4.17 minutes (compound 12), 3.31 minutes (compound    13)

Example 3 7-{4-(Trifluoromethyl)phenoxy}chroman-4-one (Compound 3-1)

Step 1

Compound 1-2 (0.80 g, 4.87 mmol) was dissolved in dichloromethane (20mL), and 4-trifluoromethylphenylboronic acid (7.40 g, 39.0 mmol),pyridine (1.96 mL, 24.4 mmol), and copper(II) acetate (1.77 g, 9.75mmol) were added to the solution. The mixture was stirred at roomtemperature overnight. A saturated aqueous ammonium chloride solutionwas added to the mixture. The mixture was filtered with Celite®. Theorganic layer in the filtrate was extracted with ethyl acetate, washedwith saturated saline, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (heptane/ethylacetate=80/20→20/80) to obtain compound 3-1 (0.18 g, 12%).

¹H NMR (400 MHz, CDCl₃, δ): 7.91 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.5 Hz,2H), 7.16 (d, J=8.5 Hz, 2H), 6.67 (dd, J=8.8, 2.2 Hz, 1H), 6.51 (d,J=2.2 Hz, 1H), 4.54 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.5 Hz, 2H).

Step 2

7-{4-(Trifluoromethyl)phenoxy}chroman-4-amine (Compound 3-2)

Compound 3-1 (0.45 g, 1.44 mmol) was dissolved in methanol (14 mL).Added to the solution were ammonium formate (1.82 g, 28.9 mmol), aceticacid (0.12 mL, 2.17 mmol), andchloro[N-{4-(dimethylamino)phenyl}-2-pyridinecarboxyamidate](pentamethylcyclopentadienyl)iridium(III) (0.026 g, 0.043 mmol), and the mixturewas stirred at 80° C. for 2.5 hours. The mixture was left to cool toroom temperature, methanol was concentrated under reduced pressure, andwater and ethyl acetate were added to the mixture. The mixture wasfiltered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25mL), and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (heptane/ethylacetate=50/50→chloroform/methanol=90/10) to obtain compound 3-2 (0.43 g,97%).

Step 3

N-[7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide (Compound 5)

Compound 5 (0.26 g, 51%) was obtained in the same manner as step 5 ofexample 1, using compound 3-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.58 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.6 Hz,1H), 7.06 (d, J=8.8 Hz, 2H), 6.61 (dd, J=8.6, 2.4 Hz, 1H), 6.51 (d,J=2.4 Hz, 1H), 6.36 (dd, J=17.0, 1.2 Hz, 1H), 6.11 (dd, J=17.0, 10.4 Hz,1H), 5.77 (d, J=6.8 Hz, 1H), 5.72 (dd, J=10.4, 1.2 Hz, 1H), 5.26-5.20(m, 1H), 4.33-4.26 (m, 1H), 4.20-4.13 (m, 1H), 2.28-2.23 (m, 1H),2.16-2.08 (m, 1H);

ESIMS m/z: [M−H]⁺ 362.

The following compounds were synthesized in accordance with thesynthesis method of compound 5.

N-[7-{4-Chloro-3-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 8)

ESIMS m/z: [M−H]⁺ 396.

N-[7-{4-(Trifluoromethoxy)phenoxy}chroman-4-yl]acrylamide (Compound 9)

ESIMS m/z: [M−H]⁺ 378.

N-{7-(4-Chloro-3-fluorophenoxy)chroman-4-yl)acrylamide (Compound 10)

ESIMS m/z: [M−H]⁺ 346.

Example 4

Step 1

7-(Benzyloxy)chroman-4-one (Compound 4-1)

Compound 1-2 (1.50 g, 9.14 mmol) was dissolved in DMF (15 mL). Benzylbromide (1.62 g, 13.7 mmol) and potassium carbonate (3.78 g, 27.4 mmol)were added to the solution, and the mixture was stirred at roomtemperature for 3 hours. Water was added to the mixture. The organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=100/0→85/15) to obtain compound 4-1 (2.00 g, 86%).

¹H NMR (300 MHz, DMSO-d₆, δ): 7.68 (d, J=8.7 Hz, 1H), 7.45-7.30 (m, 5H),6.70 (dd, J=8.7, 2.4 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 5.17 (s, 2H), 4.50(t, J=6.3 Hz, 2H), 2.70 (t, J=6.3 Hz, 2H).

Step 2

7-(Benzyloxy)chroman-4-amine (Compound 4-2)

Compound 4-2 (1.50 g, 75%) was obtained in the same manner as step 4 ofexample 1, using compound 4-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.39-7.30 (m, 5H), 7.22 (d, J=8.7 Hz, 1H),6.51 (dd, J=8.4, 2.4 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 5.03 (s, 2H),4.22-4.16 (m, 1H), 4.10-4.05 (m, 1H), 3.80 (t, J=5.1 Hz, 1H), 1.97-1.88(m, 1H), 1.72-1.64 (m, 1H).

Step 3

4-Aminochroman-7-ol (Compound 4-3)

Compound 4-2 (1.50 g, 5.88 mmol) was dissolved in ethanol (50 mL), and10% palladium carbon (0.15 g) was added to the solution. The mixture wasstirred under hydrogen atmosphere at a pressure of 60 psi at roomtemperature for 16 hours. The mixture was filtered with Celite®, and thefiltrate was concentrated under reduced pressure to obtain compound 4-3(0.60 g, 61%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.10 (d, J=8.4 Hz, 1H), 6.27 (dd, J=8.1,2.4 Hz, 1H), 6.09 (d, J=2.4 Hz, 1H), 4.20-4.08 (m, 1H), 4.07-4.02 (m,1H), 3.80 (t, J=5.1 Hz, 1H), 1.96-1.92 (m, 1H), 1.72-1.64 (m, 1H).

Step 4

7-{4-(Dimethylamino)phenoxy}chroman-4-amine (Compound 4-4)

4-Iodo-N,N-dimethylaniline (0.20 g, 1.21 mmol) was dissolved in DMSO (10mL), and compound 4-3 (0.44 g, 1.81 mmol), tripotassium phosphate (0.51g, 2.42 mmol), picolinic acid (0.014 g, 0.12 mmol), and copper(I) iodide(0.012 g, 0.06 mmol) were added to the solution under argon atmosphere.The mixture was stirred at 90° C. for 16 hours. Water was added to themixture, and the mixture was filtered with Celite®. The organic layer inthe filtrate was extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=60/40→40/60) to obtain compound 4-4 (0.13 g, 37%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.27 (d, J=7.2 Hz, 1H), 6.88 (d, J=9.2 Hz,2H), 6.74 (d, J=9.2 Hz, 2H), 6.39 (dd, J=8.0, 2.4 Hz, 1H), 6.15 (d,J=2.4 Hz, 1H), 4.22-4.18 (m, 1H), 4.09-4.07 (m, 1H), 3.80-3.78 (m, 1H),2.86 (s, 6H), 1.98-1.95 (m, 1H), 1.72-1.70 (m, 1H).

Step 5

N-[7-{4-(Dimethylamino)phenoxy}chroman-4-yl]acrylamide (Compound 6)

Compound 6 (0.055 g, 35%) was obtained in the same manner as step 5 ofexample 1, using compound 4-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.51 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.8 Hz,1H), 6.88 (d, J=9.2 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.43 (dd, J=8.8,2.8 Hz, 1H), 6.28-6.21 (m, 2H), 6.14 (dd, J=16.8, 2.4 Hz, 1H), 5.61 (dd,J=9.6, 2.4 Hz, 1H), 5.02-4.98 (m, 1H), 4.21-4.08 (m, 2H), 2.87 (m, 6H),2.09-2.00 (m, 1H), 1.98-1.84 (m, 1H);

ESIMS m/z: [M+H]⁺ 339.

The following compound was synthesized in accordance with the synthesismethod of compound 6.

N-{7-(4-Cyanophenoxy)chroman-4-yl}acrylamide (Compound 7)

ESIMS m/z: [M−70]⁺ 250.

Example 5

Step 1

7-[{6-Chloro-5-(trifluoromethyl)pyridin-2-yl}oxy]chroman-4-one (Compound5-1)

Compound 1-2 (70.0 mg, 0.426 mmol) was dissolved in DMF (1 mL), andpotassium carbonate (431 mg, 3.41 mmol) and2,6-dichloro-3-(trifluoromethyl)pyridine (0.092 mL, 0.853 mmol) wereadded to the solution. The mixture was stirred at 50° C. overnight.Water and ethyl acetate were added to the mixture. The mixture wasfiltered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25mL), and the filtrate was concentrated. The residue was purified bysilica gel column chromatography (heptane/ethylacetate=100/0→heptane/ethyl acetate=70/30) to obtain compound 5-1 (41.0mg, 28%).

¹H NMR (400 MHz, CDCl₃, δ): 8.02 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.2 Hz,1H), 6.97 (d, J=8.2 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 6.80-6.79 (m, 1H),4.58 (t, J=6.6 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H).

Step 2

7-[{6-Chloro-5-(trifluoromethyl)pyridin-2-yl}oxy]chroman-4-amine(Compound 5-2)

Compound 5-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 5-1, and used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 344.

Step 3

N-(7-[{6-Chloro-5-(trifluoromethyl)pyridin-2-yl}oxy]chroman-4-yl)acrylamide(Compound 11)

Compound 11 (20.3 mg, 43% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 5-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.96 (d, J=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz,1H), 6.88 (d, J=8.6 Hz, 1H), 6.70 (dd, J=8.6, 2.4 Hz, 1H), 6.64 (d,J=2.4 Hz, 1H), 6.36 (dd, J=16.8, 1.4 Hz, 1H), 6.13 (dd, J=16.8, 10.4 Hz,1H), 5.98 (d, J=7.2 Hz, 1H), 5.71 (dd, J=10.4, 1.4 Hz, 1H), 5.25-5.23(m, 1H), 4.32-4.29 (m, 1H), 4.21-4.15 (m, 1H), 2.30-2.20 (m, 1H),2.16-2.09 (m, 1H);

ESIMS m/z: [M−H]⁺ 397.

Example 6 N-{7-(Benzyloxy)chroman-4-yl}acrylamide (Compound 14)

Compound 14 (0.075 g, 45%) was obtained in the same manner as step 5 ofexample 1, using compound 4-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.43-7.30 (m, 5H), 7.10 (d, J=8.4 Hz, 1H),6.57 (dd, J=8.4, 2.6 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 6.33 (dd, J=16.9,1.5 Hz, 1H), 6.07 (dd, J=16.9, 10.3 Hz, 1H), 5.74 (d, J=7.3 Hz, 2H),5.68 (dd, J=10.3, 1.5 Hz, 2H), 5.14 (dd, J=12.5, 5.1 Hz, 1H), 5.02 (s,2H), 4.27-4.24 (m, 1H), 4.15-4.07 (m, 1H);

ESIMS m/z: [M+H]⁺ 310.

The following compound was synthesized in accordance with the synthesismethod of compound 14.

N-[7-{(4-Chlorobenzyl)oxy}chroman-4-yl}acrylamide (Compound 15)

ESIMS m/z: [M−70]⁺ 273.

Example 7

Step 1

7-(Cyclohexylmethoxy)chroman-4-one (Compound 7-1)

Compound 1-2 (0.10 g, 0.61 mmol) was dissolved in THF (3 mL), and,triphenylphosphine (0.32 g, 1.22 mmol), diethyl azodicarboxylate (a 2.2mol/L toluene solution, 0.55 mL, 1.22 mmol), and cyclohexanemethanol(0.15 mL, 1.22 mmol) were added to the solution. The mixture was stirredat room temperature for 3 hours. After the mixture was concentratedunder reduced pressure, the mixture was purified by silica gel columnchromatography (heptane/ethyl acetate=90/10) to obtain compound 7-1 as acrude product, which was used as it is in the next reaction.

Step 2

7-(Cyclohexylmethoxy)chroman-4-amine (Compound 7-2)

Compound 7-2 was obtained as a crude product in the same manner as step4 of example 1, using compound 7-1, and used as it is in the nextreaction.

Step 3

N-{7-(Cyclohexylmethoxy)chroman-4-yl}acrylamide (Compound 16)

Compound 16 (0.12 g, 62% over three steps) was obtained in the samemanner as step 5 of example 1, using compound 7-2.

¹H NMR (300 MHz, CDCl₃, δ): 7.08 (d, J=8.4 Hz, 1H), 6.49 (dd, J=8.4, 2.6Hz, 1H), 6.33 (dd, J=17.2, 1.8 Hz, 2H), 6.07 (dd, J=16.9, 10.3 Hz, 1H),5.74 (d, J=7.0 Hz, 1H), 5.68 (dd, J=10.3, 1.5 Hz, 1H), 5.13 (dd, J=12.3,4.9 Hz, 1H), 4.30-4.21 (m, 1H), 4.15-4.07 (m, 1H), 3.70 (d, J=6.2 Hz,2H), 2.28-2.16 (m, 1H), 2.14-2.03 (m, 1H), 1.89-1.67 (m, 5H), 1.35-1.18(m, 4H), 1.08-0.95 (m, 2H);

ESIMS m/z: [M+H]⁺ 316.

Example 8

Step 1

4-Methyl-7-phenoxychroman-4-ol (Compound 8-1)

Compound 1-3 (0.10 g, 0.41 mmol) was dissolved in THF (3 mL), and a 1.6mol/L methyllithium solution in diethyl ether (0.78 mL, 1.25 mmol) wasadded dropwise to the solution, at 0° C. under nitrogen atmosphere. Themixture was stirred at room temperature for 2 hours. A saturated aqueousammonium chloride solution was added to the mixture. The organic layerwas extracted with ethyl acetate, dried over anhydrous sodium sulfate,and concentrated under reduced pressure to obtain compound 8-1 (0.10 g,95%).

¹H NMR (400 MHz, CDCl₃, δ): 7.45-7.36 (m, 3H), 7.15-7.11 (m, 1H), 6.99(d, J=7.6 Hz, 2H), 6.52 (dd, J=8.8, 2.4 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H),5.10 (s, 1H), 4.25-4.11 (m, 2H), 1.97-1.88 (m, 2H), 1.46 (s, 3H).

Step 2

4-Azido-4-methyl-7-phenoxychromane (Compound 8-2)

Compound 8-1 (0.10 g, 0.39 mmol) was dissolved in chloroform (3 mL), andsodium azide (0.25 g, 3.90 mmol) was added to the solution. A mixedliquid of trifluoroacetic acid (0.15 mL, 1.95 mmol) and chloroform (3mL) were added dropwise to the mixture at 0° C. The mixture was stirredat room temperature for 3 hours. Water was added to the mixture. Theorganic layer was extracted with dichloromethane, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=90/10→80/20) to obtain compound 8-2 (0.06 g, 51%).

¹H NMR (400 MHz, CDCl₃, δ): 7.48-7.36 (m, 3H), 7.20-7.16 (m, 1H),7.05-7.00 (m, 2H), 6.59 (dd, J=8.4, 2.4 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H),4.28-4.11 (m, 2H), 2.18-1.89 (m, 2H), 1.65 (s, 3H).

Step 3

4-Methyl-7-phenoxychroman-4-amine (Compound 8-3)

Compound 8-2 (0.05 g, 0.17 mmol) was dissolved in THF (3 mL), and a 2mol/L lithium aluminum hydride solution in THF (0.44 mL, 0.88 mmol) wasadded dropwise to the solution at 0° C. under nitrogen atmosphere. Themixture was stirred at room temperature for 3 hours. The mixture wascooled to 0° C., and water was added to the mixture. The organic layerwas extracted with dichloromethane, dried over anhydrous sodium sulfate,and concentrated under reduced pressure to obtain compound 8-3 (0.02 g,65%).

¹H NMR (400 MHz, CDCl₃, δ): 7.50 (d, J=8.4 Hz, 1H), 7.39-7.35 (m, 2H),7.14-7.10 (m, 1H), 7.02-6.97 (m, 2H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 6.27(d, J=2.8 Hz, 1H), 4.25-4.10 (m, 2H), 1.77-1.74 (m, 2H), 1.36 (s, 3H).

Step 4

N-(4-Methyl-7-phenoxychroman-4-yl)acrylamide (Compound 17)

Compound 17 (0.08 g, 40%) was obtained in the same manner as step 5 ofexample 1, using compound 8-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.14 (s, 1H), 7.42-7.32 (m, 3H), 7.15 (t,J=7.2 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.51 (dd, J=8.4, 2.0 Hz, 1H),6.36-6.29 (m, 2H), 6.01 (dd, J=17.2, 2.0 Hz, 1H), 5.51 (dd, J=10.0, 1.6Hz, 1H), 4.16-4.13 (m, 2H), 2.84-2.78 (m, 1H), 1.80-1.74 (m, 1H), 1.65(s, 3H);

ESIMS m/z: [M−70]⁺ 239.

Example 9

Step 1

7-(4-Chlorophenoxy)-2,2-dimethylchroman-4-one (Compound 9-1)

Compound 9-1 (170 mg, 72%) was obtained in the same manner as step 1 ofexample 3, using commercially available7-hydroxy-2,2-dimethylchroman-4-one.

¹H NMR (400 MHz, CDCl₃, δ): 7.84 (d, J=8.6 Hz, 1H), 7.37-7.35 (m, 2H),7.04-7.02 (m, 2H), 6.59 (dd, J=8.6, 2.3 Hz, 1H), 6.36 (d, J=2.3 Hz, 1H),2.68 (s, 2H), 1.44 (s, 6H).

Step 2

7-(4-Chlorophenoxy)-2,2-dimethylchroman-4-amine (Compound 9-2)

Compound 9-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 9-1, and used as it is in the nextreaction.

ESIMS m/z: [M−17]⁺ 287.

Step 3

N-{7-(4-Chlorophenoxy)-2,2-dimethylchroman-4-yl}acrylamide (Compound 18)

Compound 18 (38.0 mg, 35% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 9-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.31-7.26 (m, 2H), 7.16 (d, J=8.6 Hz, 1H),6.96-6.93 (m, 2H), 6.54 (dd, J=8.6, 2.7 Hz, 1H), 6.38 (d, J=2.7 Hz, 1H),6.34 (dd, J=17.0, 1.4 Hz, 1H), 6.14 (dd, J=17.0, 10.4 Hz, 1H), 5.81 (d,J=8.6 Hz, 1H), 5.70 (dd, J=10.4, 1.4 Hz, 1H), 5.35-5.32 (m, 1H), 2.23(dd, J=13.3, 6.3 Hz, 1H), 1.71 (dd, J=13.3, 10.9 Hz, 1H), 1.40 (s, 3H),1.33 (s, 3H);

ESIMS m/z: [M−H]⁺ 356.

Example 10

Step 1

7-Hydroxy-2-methylchroman-4-one (Compound 10-1)

Trifluoromethanesulfonic acid (3.2 mL) was added to a mixture ofresorcinol (500 mg, 4.54 mmol) and crotonic acid (430 mg, 4.99 mmol),and the mixture was stirred at 80° C. for 2 hours. The mixture left tocool to room temperature was gradually added to a 2 mol/L aqueous sodiumhydroxide solution. The organic layer was extracted with ethyl acetate,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(heptane/ethyl acetate=100/0→heptane/ethyl acetate=50/50) to obtaincompound 10-1 (55.0 mg, 7%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.59 (d, J=8.6 Hz, 1H), 6.46 (dd, J=8.6,2.3 Hz, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.58-4.55 (m, 1H), 2.62-2.58 (m,2H), 1.39 (d, J=6.3 Hz, 3H).

Step 2

2-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-one (Compound 10-2)

Compound 10-2 (66.5 mg, 83%) was obtained in the same manner as step 1of example 3, using compound 10-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.65 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz,1H), 7.16 (d, J=8.5 Hz, 2H), 6.67 (dd, J=8.5, 2.5 Hz, 1H), 6.49 (d,J=2.5 Hz, 1H), 4.62-4.59 (m, 1H), 2.68-2.67 (m, 2H), 1.50 (d, J=6.3 Hz,3H).

Step 3

2-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-amine (Compound 10-3)

Compound 10-3 was obtained as an unpurified crude product in the samemanner as step 2 of example 3, using compound 10-2, and used as it is inthe next reaction.

ESIMS m/z: [M−16]⁺ 307.

Step 4

cis-N-[2-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 19)trans-N-[2-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 20)

Compound 19 (16.8 mg, 22% over two steps) and compound 20 (12.9 mg, 17%over two steps) were obtained in the same manner as step 5 of example 1,using compound 10-3.

Compound 19: ¹H NMR (400 MHz, CDCl₃, δ): 7.57 (d, J=8.6 Hz, 2H), 7.21(dd, J=8.6, 0.9 Hz, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.60 (dd, J=8.6, 2.5Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 6.38 (dd, J=17.0, 1.1 Hz, 1H), 6.14(dd, J=17.0, 10.4 Hz, 1H), 5.74 (dd, J=10.4, 1.4 Hz, 1H), 5.64 (d, J=8.6Hz, 1H), 5.47-5.41 (m, 1H), 4.34-4.28 (m, 1H), 2.43-2.40 (m, 1H),1.65-1.62 (m, 1H), 1.41 (d, J=6.3 Hz, 3H)

ESIMS m/z: [M−H]⁺ 376.

Compound 20: ¹H NMR (400 MHz, CDCl₃, δ): 7.58 (d, J=8.6 Hz, 2H), 7.23(d, J=8.6 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.62 (dd, J=8.6, 2.5 Hz, 1H),6.51 (d, J=2.5 Hz, 1H), 6.35 (dd, J=17.0, 1.4 Hz, 1H), 6.08 (dd, J=17.0,10.4 Hz, 1H), 5.81 (d, J=6.8 Hz, 1H), 5.70 (dd, J=10.4, 1.4 Hz, 1H),5.15-5.11 (m, 1H), 4.20-4.13 (m, 1H), 2.23 (dt, J=14.3, 2.0 Hz, 1H),1.90-1.86 (m, 1H), 1.43 (d, J=6.3 Hz, 3H)

ESIMS m/z: [M−H]⁺ 376.

Example 11

Step 1

3-Fluoro-7-(4-(trifluoromethyl)phenoxy)chroman-4-one (Compound 11-1)

Compound 3-1 (110 mg, 0.357 mmol) was dissolved in methanol (1 mL), and1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane-1,4-diiumtetrafluoroborate (50% on aluminum oxide, 276 mg, 0.428 mmol) was addedto the solution. The mixture was stirred at 80° C. for 2 hours, followedby filtration, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(heptane/ethyl acetate=100/0→heptane/ethyl acetate=60/40) to obtaincompound 114 (90.0 mg, 77%).

¹H NMR (400 MHz, CDCl₃, δ): 7.94 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.6 Hz,2H), 7.17 (d, J=8.6 Hz, 2H), 6.74 (dd, J=8.6, 2.3 Hz, 1H), 6.52 (d,J=2.3 Hz, 1H), 5.11 (ddd, J=47.1, 4.2, 2.1 Hz, 1H), 4.62-4.56 (m, 2H).

Step 2

3-Fluoro-7-(4-(trifluoromethyl)phenoxy)chroman-4-amine (Compound 11-2)

Compound 11-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 11-1, and used as it is in the nextreaction.

Step 3

cis-N-[3-Fluoro-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 21)trans-N-[3-Fluoro-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 22)

Compound 21 (44.5 mg, 41% over two steps) and compound 22 (5.5 mg, 5%over two steps) were obtained in the same manner as step 5 of example 1,using compound 11-2.

Compound 21: ¹H NMR (400 MHz, CDCl₃, δ): 7.58 (d, J=8.6 Hz, 2H), 7.20(d, J=8.6 Hz, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.65 (dd, J=8.6, 2.7 Hz, 1H),6.55 (d, J=2.7 Hz, 1H), 6.43 (dd, J=17.0, 0.9 Hz, 1H), 6.23 (dd, J=17.0,10.2 Hz, 1H), 6.10 (d, J=9.1 Hz, 1H), 5.80 (dd, J=10.2, 0.9 Hz, 1H),5.58 (ddd, J=29.9, 9.5, 3.2 Hz, 1H), 5.02 (dt, J=48.5, 3.2 Hz, 1H),4.59-4.52 (m, 1H), 4.26 (dd, J=39.0, 13.1 Hz, 1H);

ESIMS m/z: [M−H]⁺ 380.

Compound 22: ¹H NMR (400 MHz, CDCl₃, δ): 7.59 (d, J=8.6 Hz, 2H), 7.23(d, J=8.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 6.68 (dd, J=8.4, 2.5 Hz, 1H),6.58 (d, J=2.3 Hz, 1H), 6.38 (dd, J=16.8, 1.4 Hz, 1H), 6.09 (dd, J=17.0,10.2 Hz, 1H), 5.75 (dd, J=10.4, 1.4 Hz, 1H), 5.65 (d, J=5.4 Hz, 1H),5.21-5.19 (m, 1H), 5.03 (dtd, J=45.2, 3.4, 1.4 Hz, 1H), 4.49-4.42 (m,1H), 4.15 (ddd, J=36.0, 12.9, 1.1 Hz, 1H);

ESIMS m/z: [M−H]⁺ 380.

Example 12

Step 1

3-Chloro-1-(2,4-dihydroxy-5-methylphenyl)propan-1-one (Compound 12-1)

Compound 12-1 (0.25 g, 48%) was obtained in the same manner as step 1 ofexample 1, using 4-methylbenzene-1,3-diol.

¹H NMR (300 MHz, DMSO-d₆, δ): 10.68 (s, 1H), 12.29 (s, 1H), 7.66 (s,1H), 6.31 (s, 1H), 3.91 (t, J=6.3 Hz, 2H), 3.48 (t, J=6.3 Hz, 2H), 2.06(s, 3H).

Step 2

7-Hydroxy-6-methylchroman-4-one (Compound 12-2)

Compound 12-2 (0.15 g, 72%) was obtained in the same manner as step 2 ofexample 1, using compound 12-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 10.54 (s, 1H), 7.46 (s, 1H), 6.34 (s, 1H),4.42 (t, J=6.3 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 2.05 (s, 3H).

Step 3

7-(Benzyloxy)-6-methylchroman-4-one (Compound 12-3)

Compound 12-3 (0.55 g, 76%) was obtained in the same manner as step 1 ofexample 4, using compound 12-2.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.53 (s, 1H), 7.47-7.31 (m, 5H), 6.62 (s,1H), 5.19 (s, 2H), 4.47 (t, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 2.13(s, 3H).

Step 4

7-(Benzyloxy)-6-methylchroman-4-amine (Compound 12-4)

Compound 12-4 (0.40 g, 78%) was obtained in the same manner as step 4 ofexample 1, using compound 12-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.43-7.30 (m, 5H), 7.09 (s, 1H), 6.34 (s,1H), 5.04 (s, 2H), 4.20-4.02 (m, 2H), 3.77 (t, J=5.1 Hz, 1H), 2.10 (s,3H), 2.10-1.83 (m, 1H), 1.96-1.83 (m, 1H).

Step 5

4-Amino-6-methylchroman-7-ol (Compound 12-5)

Compound 12-5 (0.18 g, 65%) was obtained in the same manner as step 3 ofexample 4, using compound 12-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.02 (s, 1H), 6.18 (s, 1H), 4.17-3.99 (m,2H), 3.92 (bs, 1H), 2.01 (s, 3H), 1.96-1.92 (m, 1H), 1.84-1.71 (m, 1H).

Step 6

7-(4-Chlorophenoxy)-6-methylchroman-4-amine (Compound 12-6)

Compound 12-6 (0.09 g, 56%) was obtained in the same manner as step 4 ofexample 4, using compound 12-5.

ESIMS m/z: [M−16]⁺ 273.

Step 7 N-{7-(4-Chlorophenoxy)-6-methylchroman-4-yl}acrylamide (Compound23)

Compound 23 (0.025 g, 23%) was obtained in the same manner as step 5 ofexample 1, using compound 12-6.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.56 (d, J=8.0 Hz, 1H), 7.40 (d, J=9.2 Hz,2H), 7.08 (s, 1H), 6.89 (d, J=9.2 Hz, 2H), 6.34-6.24 (m, 2H), 6.16 (d,J=17.2, 2.4 Hz, 1H), 5.63 (dd, J=10.0, 2.4 Hz, 1H), 5.06-5.01 (m, 1H),4.23-4.10 (m, 2H), 2.09-2.03 (m, 4H), 1.92-1.85 (m, 1H)

ESIMS m/z: [M−70]⁺ 273.

Example 13

Step 1

6-Hydroxychroman-4-one (Compound 13-1)

A 33% hydrogen bromide solution in acetic acid (10.0 mL) was added tocommercially available 6-methoxychroman-4-one (0.30 g, 1.68 mmol), andthe mixture was stirred at 100° C. for 12 hours. The mixture was cooledto room temperature, a saturated aqueous sodium bicarbonate solution wasadded to the mixture. The organic layer was extracted with ethylacetate, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=70/30→60/40) to obtain compound13-1 (0.20 g, 72%).

¹H NMR (300 MHz, DMSO-d₆, δ): 9.36 (s, 1H), 7.07 (d, J=3.0 Hz, 1H), 6.99(dd, J=8.7, 3.0 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 4.42 (t, J=6.6 Hz, 2H),2.72 (t, J=6.6 Hz, 2H).

Step 2

6-(4-Chlorophenoxy)chroman-4-one (Compound 13-2)

Compound 13-2 (0.310 g, 32%) was obtained in the same manner as step 3of example 1, using compound 13-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.44-7.41 (m, 2H), 7.34 (dd, J=9.0, 3.3Hz, 1H), 7.25 (d, J=3.0 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.11-6.99 (m,2H), 4.54 (t, J=6.3 Hz, 2H), 2.79 (t, J=6.3 Hz, 2H).

Step 3

6-(4-Chlorophenoxy)chroman-4-amine (Compound 13-3)

Compound 13-3 was obtained as a crude product in the same manner as step4 of example 1, using compound 13-2, and used as it is in the nextreaction.

ESIMS m/z: [M−16]⁺ 259.

Step 4

N-{6-(4-Chlorophenoxy)chroman-4-yl}acrylamide (Compound 24)

Compound 24 (0.120 g, 35% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 13-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.59 (d, J=8.1 Hz, 1H), 7.37 (d, J=9.0 Hz,2H), 6.94-6.89 (m, 3H), 6.85-6.83 (m, 2H), 6.28-6.19 (m, 1H), 6.15-6.09(m, 1H), 5.61 (dd, J=9.6, 2.4 Hz, 1H), 5.10-5.03 (m, 1H), 4.24-4.18 (m,2H), 2.09-2.06 (m, 1H), 1.95-1.87 (m, 1H)

ESIMS m/z: [M+H]⁺ 330.

Example 14

Step 1

4-Aminochroman-8-ol hydrobromide (Compound 14-1)

A saturated aqueous sodium bicarbonate solution was added tocommercially available 8-methoxychroman-4-amine hydrochloride (500 mg,2.32 mol). The organic layer was extracted with chloroform and filteredwith Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL). Thefiltrate was concentrated under reduced pressure. The residue wasdissolved in dichloromethane (4 mL) and the solution was cooled to −78°C. A 1 mol/L boron tribromide solution in dichloromethane (4.64 mL, 4.64mmol) was added to the solution, and the mixture was stirred at −78° C.for 2 hours. To the reaction liquid, methanol was added at −78° C., andthe mixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography(chloroform/methanol=90/10→chloroform/methanol=70/30) to obtain compound14-1 (403 mg, 71%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.35 (br, 2H), 6.89-6.88 (m, 1H), 6.78 (s,1H), 6.77 (s, 1H), 4.49-4.48 (m, 1H), 4.27-4.22 (m, 2H), 2.28-2.23 (m,1H), 2.12-2.05 (m, 1H).

Step 2

8-(4-(Trifluoromethyl)phenoxy)chroman-4-amine (Compound 14-2)

Compound 14-2 (20.7 mg, 17%) was obtained in the same manner as step 4of example 4, using compound 14-1 and 1-iodo-4-(trifluoromethyl)benzene.

¹H NMR (400 MHz, CDCl₃, δ): 7.53 (d, J=8.6 Hz, 2H), 7.21 (dd, J=6.3, 3.2Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 6.92-6.91 (m, 2H), 4.31-4.20 (m, 2H),4.12 (t, J=5.0 Hz, 1H), 2.20-2.12 (m, 1H), 1.90-1.82 (m, 1H).

Step 3

N-[8-{4-(Trifluoromethyl)phenoxy}chroman-4-yl]acrylamide (Compound 25)

Compound 25 (17.3 mg, 87%) was obtained in the same manner as step 5 ofexample 1, using compound 14-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.55 (d, J=8.5 Hz, 2H), 7.13 (dt, J=7.6, 0.9Hz, 1H), 6.98 (d, J=8.1 Hz, 3H), 6.93-6.91 (m, 1H), 6.38 (d, J=16.8 Hz,1H), 6.12 (dd, J=16.8, 10.5 Hz, 1H), 5.79-5.77 (m, 1H), 5.74 (d, J=10.5Hz, 1H), 5.32 (dd, J=13.2, 5.6 Hz, 1H), 4.32-4.26 (m, 1H), 4.18-4.14 (m,1H), 2.29-2.26 (m, 1H), 2.14-2.11 (m, 1H)

ESIMS m/z: [M−H]⁺ 362.

Example 15

Step 1

7-(4-Chlorophenoxy)chroman-4-ol (Compound 15-1)

Compound 2-1 (0.24 g, 0.87 mmol) was dissolved in methanol (5 mL), andsodium borohydride (0.16 g, 4.37 mmol) was added to the solution at 0°C. The mixture was stirred at room temperature for 2 hours. Water wasadded to the mixture. The organic layer was extracted withdichloromethane, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain compound 15-1 (0.10 g, 41%).

¹H NMR (300 MHz, DMSO-d₆, δ): 7.42 (dd, J=6.6, 2.1 Hz, 2H), 7.31 (d,J=8.4 Hz, 1H), 7.00 (d, J=6.9 Hz, 2H), 6.54 (dd, J=8.1, 2.4 Hz, 1H),6.38 (d, J=2.4 Hz, 1H), 5.37 (d, J=4.5 Hz, 1H), 4.61-4.59 (m, 1H),4.20-4.16 (m, 2H), 2.04-1.81 (m, 2H).

Step 2

7-(4-Chlorophenoxy)chroman-4-carbonitrile (Compound 15-2)

Compound 15-1 (0.10 g, 0.36 mmol) was dissolved in dichloromethane (3mL), and zinc(II) iodide (0.34 g, 1.08 mmol) and trimethylsilyl cyanide(0.06 mL, 0.54 mmol) were added to the solution. The mixture was stirredat room temperature for 18 hours. Water was is added to the mixture. Theorganic layer was extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtaincompound 15-2 (0.06 g, 58%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.20 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz,1H), 6.82 (d, J=9.2 Hz, 2H), 6.39 (dd, J=8.4, 2.0 Hz, 1H), 6.23 (d,J=2.4 Hz, 1H), 4.19 (t, J=6.0 Hz, 1H), 3.99-3.95 (m, 2H), 2.09-1.94 (m,2H).

Step 3

{7-(4-Chlorophenoxy)chroman-4-yl}methanamine (Compound 15-3)

Compound 15-2 (0.06 g, 0.21 mmol) was dissolved in ethanol (5 mL), andRaney nickel (0.05 g) and ammonia water (0.1 mL) were added to thesolution. The mixture was stirred under hydrogen atmosphere at roomtemperature for 2 hours. The mixture was filtered with Celite®, and thefiltrate was concentrated under reduced pressure to obtain compound 15-3(0.06 g) as a crude product.

ESIMS m/z: [M+H]⁺ 290.

Step 4

N-[{7-(4-Chlorophenoxy)chroman-4-yl}methyl]acrylamide (Compound 26)

Compound 26 (0.03 g, 42% over two steps) was obtained in the same manneras step 5 of example 1, using compound 15-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.34 (bs, 1H), 7.42 (d, J=8.8 Hz, 2H),7.19 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.54 (dd, J=8.0, 2.0 Hz,1H), 6.4 (d, J=2.0 Hz, 1H), 6.26 (dd, J=17.2, 10.0 Hz, 1H), 6.10 (dd,J=17.2, 2.0 Hz, 1H), 5.61 (dd, J=10.0, 1.6 Hz, 1H), 4.18-4.09 (m, 2H),3.49-3.44 (m, 1H), 3.30-3.25 (m, 1H), 2.91-2.90 (m, 1H), 1.93-1.88 (m,1H), 1.81-1.78 (m, 1H);

ESIMS m/z: [M+H]⁺ 344.

Example 16

Step 1

3-Chloro-1-(2,4-dihydroxy-3-methylphenyl)propan-1-one (Compound 16-1)

Compound 16-1 (0.60 g, 34%) was obtained in the same manner as step 1 ofexample 1, using 2-methylbenzene-1,3-diol.

ESIMS m/z: [M+H]⁺ 214.

Step 2

7-Hydroxy-8-methylchroman-4-one (Compound 16-2)

Compound 16-2 (0.30 g, 60%) was obtained in the same manner as step 2 ofexample 1, using compound 16-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 10.4 (s, 1H), 7.48 (d, J=8.7 Hz, 1H), 6.55(d, J=8.7 Hz, 1H), 4.50-4.46 (m, 2H), 2.65 (t, J=6.0 Hz, 2H), 1.97 (s,3H).

Step 3

7-(4-Chlorophenoxy)-8-methylchroman-4-one (Compound 16-3)

Compound 16-3 (0.20 g, 45%) was obtained in the same manner as step 3 ofexample 1, using compound 16-2.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.46 (d, J=8.7 Hz, 1H), 7.18 (d, J=8.7 Hz,2H), 7.03 (d, J=8.7 Hz, 1H), 6.76 (d, J=8.7 Hz, 2H), 4.60 (t, J=6.3 Hz,2H), 3.39 (t, J=6.0 Hz, 1H), 2.77 (d, J=6.3 Hz, 1H), 2.09 (s, 3H).

Step 4

7-(4-Chlorophenoxy)-8-methylchroman-4-amine (Compound 16-4)

Compound 16-4 (0.30 g, 60%) was obtained in the same manner as step 4 ofexample 1, using compound 16-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.36 (d, J=9.0 Hz, 2H), 7.25 (d, J=8.4 Hz,1H), 6.85 (d, J=9.0 Hz, 2H), 6.50 (d, J=8.4 Hz, 1H), 4.35-4.18 (m, 2H),3.88 (t, J=5.1 Hz, 1H), 2.00-1.94 (m, 1H), 1.92 (s, 3H), 1.79-1.70 (m,1H).

Step 5

N-{7-(4-Chlorophenoxy)-8-methylchroman-4-yl}acrylamide (Compound 27)

Compound 27 (0.17 g, 48%) was obtained in the same manner as step 5 ofexample 1, using compound 16-4.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.60 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.7 Hz,2H), 7.03 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 6.54 (d, J=8.7 Hz,1H), 6.30-6.12 (m, 2H), 5.63 (dd, J=9.6, 2.7 Hz, 1H), 5.10-5.08 (m, 1H),4.34-4.09 (m, 2H), 2.11-2.06 (m, 1H), 1.96-1.88 (m, 4H)

ESIMS m/z: [M−70]⁺ 273.

Example 17

Step 1

8-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-one (Compound 17-1)

Compound 17-1 (177 mg, 65%) was obtained in the same manner as step 1 ofexample 3, using compound 16-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.78 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.6 Hz,2H), 7.03 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.8 Hz, 1H), 4.61 (t, J=6.3 Hz,2H), 2.82 (t, J=6.3 Hz, 2H), 2.14 (s, 3H).

Step 2

8-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-amine (Compound 17-2)

Compound 17-2 (140 mg, 73%) was obtained in the same manner as step 2 ofexample 3, using compound 17-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.52 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.3 Hz,1H), 6.93 (d, J=8.6 Hz, 2H), 6.57 (d, J=8.3 Hz, 1H), 4.38-4.28 (m, 2H),4.08 (t, J=5.1 Hz, 1H), 2.18-2.15 (m, 1H), 2.02 (s, 3H), 1.89-1.82 (m,1H).

Step 3

N-[8-Methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 28)

Compound 17-2 (70 mg, 0.22 mmol) was dissolved in DMA (2 mL), andacryloyl chloride (0.026 mL, 0.33 mmol) was added to the mixed solution.The mixture was stirred at room temperature for 2 hours. Water was addedto the mixture, and a precipitated solid was filtered off, washed withwater, and dried to obtain a crude product. The crude product waspurified by silica gel column chromatography (heptane/ethylacetate=80/20→50/50) to obtain compound 28 (34 mg, 42%).

¹H NMR (400 MHz, CDCl₃, δ): 7.53 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz,1H), 6.93 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.8 Hz, 1H), 6.36 (dd, J=17.0,1.5 Hz, 1H), 6.10 (dd, J=17.0, 10.4 Hz, 1H), 5.77 (s, 1H), 5.71 (dd,J=10.4, 1.5 Hz, 1H), 5.25-5.22 (m, 1H), 4.39-4.34 (m, 1H), 4.24-4.18 (m,1H), 2.30-2.22 (m, 1H), 2.17-2.10 (m, 1H), 2.03 (s, 3H)

ESIMS m/z: [M−H]⁺ 376.

Example 18(E)-4,4,4-Trifluoro-N-[8-methyl-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]-2-butenamide(Compound 29)

Compound 29 (61 mg, 63%) was obtained in the same manner as step 3 ofexample 17, using compound 17-2 and commercially available(E)-4,4,4-trifluoro-2-butenoyl chloride.

¹H NMR (400 MHz, CDCl₃, δ): 7.54 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.3 Hz,1H), 6.93 (d, J=8.8 Hz, 2H), 6.85-6.81 (m, 1H), 6.57 (d, J=8.3 Hz, 1H),6.50-6.46 (m, 1H), 6.00 (d, J=7.8 Hz, 1H), 5.25-5.22 (m, 1H), 4.41-4.37(m, 1H), 4.23-4.17 (m, 1H), 2.31-2.26 (m, 1H), 2.17-2.11 (m, 1H), 2.04(s, 3H);

ESIMS m/z: [M H]⁺ 444.

Example 19

Step 1

2-Fluorobenzene-1,3-diol (Compound 19-1)

2-Fluoro-3-methoxyphenol (0.50 g, 3.52 mmol) was dissolved indichloromethane (10 mL). A 1 mol/L boron tribromide in dichloromethane(17.6 mL, 17.6 mmol) was added dropwise to the mixture at −78° C. undernitrogen atmosphere, and the mixture was stirred at room temperature for18 hours. The mixture was cooled to −78° C., and water was added to themixture. The organic layer was extracted with dichloromethane, driedover anhydrous sodium sulfate, and concentrated under reduced pressureto obtain compound 19-1 (0.45 g, 89%).

¹H NMR (400 MHz, DMSO-d₆, δ): 9.57 (s, 2H), 6.73-6.68 (m, 1H), 6.38-6.34(m, 2H).

Step 2

3-Chloro-1-(3-fluoro-2,4-dihydroxyphenyl)propan-1-one (Compound 19-2)

Compound 19-2 (0.65 g, 85%) was obtained in the same manner as step 1 ofexample 1, using compound 19-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 12.24 (s, 1H), 11.18 (s, 1H), 7.64-7.61(m, 1H), 6.56-6.52 (m, 1H), 3.91 (t, J=6.4 Hz, 2H), 3.52 (t, J=6.4 Hz,2H).

Step 3

8-Fluoro-7-hydroxychroman-4-one (Compound 19-3)

Compound 19-3 (0.45 g, 83%) was obtained in the same manner as step 2 ofexample 1, using compound 19-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 11.05 (s, 1H), 7.44-7.41 (m, 1H),6.66-6.62 (m, 1H), 4.57 (t, J=6.4 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H).

Step 4

7-(4-Chlorophenoxy)-8-fluorochroman-4-one (Compound 19-4)

Compound 19-4 was obtained as a crude product in the same manner as step1 of example 3, using compound 19-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.57 (dd, J=9.0, 2.1 Hz, 1H), 7.49 (d,J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.72-6.67 (m, 1H), 4.68 (t, J=6.3Hz, 2H), 2.85 (t, J=6.6 Hz, 2H).

Step 5

7-(4-Chlorophenoxy)-8-fluorochroman-4-amine (Compound 19-5)

Compound 19-5 was obtained as a crude product in the same manner as step4 of example 1, using compound 19-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.40-7.30 (m, 3H), 6.95 (d, J=8.8 Hz, 2H),6.68-6.64 (m, 1H), 4.34-4.09 (m, 3H), 2.04-2.00 (m, 1H), 1.80-1.76 (m,1H);

ESIMS m/z: [M−16]⁺ 277.

Step 6

N-{7-(4-Chlorophenoxy)-8-fluorochroman-4-yl}acrylamide (Compound 30)

Compound 30 (0.025 g, 4% over three steps) was obtained in the samemanner as step 5 of example 1, using compound 19-5.

¹H NMR (400 MHz, CDCl₃, δ): 7.29-7.25 (m, 2H), 6.97-6.89 (m, 3H),6.59-6.55 (m, 1H), 6.36 (dd, J=16.8, 1.2 Hz, 1H), 6.10 (dd, J=16.8, 10.0Hz, 1H), 5.81-5.71 (m, 2H), 5.30-5.20 (m, 1H), 4.43-4.38 (m, 1H),4.29-4.23 (m, 1H), 2.32-2.24 (m, 1H), 2.18-2.11 (m, 1H);

ESIMS m/z: [M−70]⁺ 277.

Example 20

Step 1

8-Fluoro-7-{4-(trifluoromethyl)phenoxy}chroman-4-one (Compound 20-1)

Compound 20-1 (0.02 g, 11%) was obtained in the same manner as step 1 ofexample 3, using compound 19-3.

1H NMR (400 MHz, CDCl₃, δ): 7.70-7.62 (m, 3H), 7.12 (d, J=8.4 Hz, 2H),6.69-6.65 (m, 1H), 4.70-4.66 (m, 2H), 2.89-2.86 (m, 2H).

Step 2

8-Fluoro-7-{4-(trifluoromethyl)phenoxy}chroman-4-amine (Compound 20-2)

Compound 20-2 (0.12 g, 67%) was obtained in the same manner as step 4 ofexample 1, using compound 20-1.

¹H NMR (300 MHz, CDCl₃, δ): 7.57-7.11 (m, 3H), 7.02 (d, J=8.7 Hz, 2H),6.68-6.62 (m, 1H), 4.41-4.08 (m, 3H), 2.25-2.15 (m, 1H), 1.95-1.87 (m,1H).

Step 3

N-[8-Fluoro-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compound 31)

Compound 31 (0.05 g, 39%) was obtained in the same manner as step 5 ofexample 1, using compound 20-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.66 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.4 Hz,2H), 7.11 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.8 Hz, 1H), 6.82 (t, J=7.6 Hz,1H), 6.30-6.15 (m, 2H), 5.66 (dd, J=9.6, 2.4 Hz, 1H), 5.15-5.13 (m, 1H),4.39-4.30 (m, 2H), 2.16-2.12 (m, 1H), 1.98-1.96 (m, 1H);

ESIMS m/z: [M−70]⁺ 311.

Example 21

Step 1

2-Methoxybenzene-1,3-diol (Compound 21-1)

Benzene-1,2,3-triol (2.00 g, 15.87 mmol) was dissolved in acetone (20mL), and potassium hydrogen carbonate (1.74 g, 17.46 mmol) and methyliodide (2.25 g, 15.83 mmol) were added to the solution. The mixture wasstirred at 50° C. for 24 hours. The mixture was filtered with Celite®,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=100/0→70/30) to obtain compound 21-1 (0.50 g, 22%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.98 (s, 2H), 6.65 (t, J=8.4 Hz, 1H), 6.27(d, J=8.0 Hz, 2H), 3.65 (s, 3H).

Step 2

3-Chloro-1-(2,4-dihydroxy-3-methoxyphenyl)propan-1-one (Compound 21-2)

Compound 21-2 (0.77 g, 46%) was obtained in the same manner as step 1 ofexample 1, using compound 21-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 12.39 (s, 1H), 10.50 (s, 1H), 7.57 (d,J=8.8 Hz, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.90-3.88 (m, 2H), 3.71 (s, 3H),3.51-3.48 (m, 2H).

Step 3

7-Hydroxy-8-methoxychroman-4-one (Compound 21-3)

Compound 21-3 (0.10 g, 59%) was obtained in the same manner as step 2 ofexample 1, using compound 21-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.30 (s, 1H), 7.38 (d, J=8.8 Hz, 1H),6.55 (d, J=8.8 Hz 1H), 4.52 (t, J=6.4 Hz, 2H), 3.70 (s, 3H), 2.68 (t,J=5.6 Hz, 2H).

Step 4

7-(4-Chlorophenoxy)-8-methoxychroman-4-one (Compound 21-4)

Compound 21-4 (0.30 g, 58%) was obtained in the same manner as step 1 ofexample 3, using compound 21-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.54-7.46 (m, 3H), 7.06 (d, J=8.7 Hz, 2H),6.63 (d, J=9.0 Hz, 1H), 4.62 (t, J=6.6 Hz, 2H), 3.73 (s, 3H), 2.80 (t,J=6.3 Hz, 2H).

Step 5

7-(4-Chlorophenoxy)-8-methoxychroman-4-amine (Compound 21-5)

Compound 21-5 (0.20 g, 70%) was obtained in the same manner as step 4 ofexample 1, using compound 21-4.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.36 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz,1H), 6.88 (d, J=9.0 Hz, 2H), 6.58 (d, J=8.7 Hz, 1H), 4.32-4.10 (m, 2H),3.90-3.86 (m, 1H), 3.59 (s, 3H), 2.03-1.96 (m, 1H), 1.79-1.71 (m, 1H).

Step 6

N-{7-(4-Chlorophenoxy)-8-methoxychroman-4-yl}acrylamide (Compound 32)

Compound 32 (0.09 g, 38%) was obtained in the same manner as step 5 ofexample 1, using compound 21-5.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.62 (d, J=8.1 Hz, 1H), 7.38 (d, J=9.0 Hz,2H), 6.91-6.88 (m, 3H), 6.62 (d, J=8.7 Hz, 1H), 6.31-6.12 (m, 2H), 5.63(dd, J=8.7, 2.7 Hz, 1H), 5.08 (d, J=7.8 Hz, 1H) 4.36-4.20 (m, 2H), 3.6(s, 3H), 2.12-2.06 (m, 1H), 1.94-1.90 (m, 1H);

ESIMS m/z: [M−70]⁺ 289.

Example 22

Step 1

8-Methoxy-7-{4-(trifluoromethyl)phenoxy}-chroman-4-one (Compound 22-1)

Compound 22-1 (0.38 g, 66%) was obtained in the same manner as step 1 ofexample 3, using compound 21-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.75 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz,1H), 7.17 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.7 Hz, 1H), 4.65 (t, J=6.6 Hz,2H), 3.72 (s, 3H), 2.82 (t, J=6.6 Hz, 2H).

Step 2

8-Methoxy-7-{4-(trifluoromethyl)phenoxy}-chroman-4-amine (Compound 22-2)

Compound 22-2 (0.34 g, 90%) was obtained in the same manner as step 4 ofexample 1, using compound 22-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.60 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.4 Hz,1H), 7.02 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 4.34-4.19 (m, 2H),3.92-3.88 (m, 1H), 3.59 (s, 3H), 2.06-1.99 (m, 1H), 1.82-1.73 (m, 1H).

Step 3

N-[8-Methoxy-7-{4-(trifluoroethyl)phenoxy}chroman-4-yl]acrylamide(Compound 33)

Compound 33 (0.12 g, 28%) was obtained in the same manner as step 5 ofexample 1, using compound 22-2.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.60 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.7 Hz,2H), 7.00 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz,1H), 6.32-6.13 (m, 2H), 5.64 (dd, J=9.6, 2.7 Hz, 1H), 5.13 (d, J=5.7 Hz,1H), 4.37-4.22 (m, 2H), 3.60 (s, 3H), 2.14-2.08 (m, 1H) 1.99-1.91 (m,1H);

ESIMS m/z: [M−70]⁺ 323.

Example 23

Step 1

5-Methoxy-2H-chromene-3-carbonitrile (Compound 23-1)

Acrylonitrile (10 mL) and 1,4-diazabicyclo[2.2.2]octane (0.55 g, 4.93mmol) were added to commercially available2-hydroxy-6-methoxybenzaldehyde(0.50 g, 3.28 mmol), and the mixture wasstirred at 85° C. for 16 hours. The mixture was cooled to roomtemperature, and water was added to the mixture. The organic layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=80/20→70/30) to obtaincompound 23-1 (0.30 g, 48%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.55 (d, J=0.8 Hz, 1H), 7.30 (t, J=8.4 Hz,1H), 6.67 (dd, J=8.4, 0.4 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 4.80 (d,J=1.2 Hz, 2H), 3.83 (s, 3H)

Step 2

5-Methoxy-2H-chromene-3-carboxylic acid (Compound 23-2)

A 3 mol/L aqueous sodium hydroxide solution (10 mL) was added tocompound 23-1 (0.30 g, 1.64 mmol), and the mixture was refluxed for 5hours. The mixture was cooled to room temperature, and 2 mol/Lhydrochloric acid (10.0 mL) was added to the mixture. The precipitatedsolid was filtered off, washed with water, and dried under reducedpressure to obtain compound 23-2 (0.25 g, 72%).

¹H NMR (400 MHz, DMSO-d₆, δ): 12.75 (s, 1H), 7.56 (d, J=0.8 Hz, 1H),7.24 (t, J=8.4 Hz, 1H), 6.62 (dd, J=8.4, 0.4 Hz, 1H), 6.49-6.47 (m, 1H),4.84 (d, J=1.6 Hz, 2H), 3.82 (s, 3H).

Step 3

tert-Butyl (5-methoxy-2H-chromen-3-yl)carbamate (Compound 23-3)

tert-Butanol (25 mL) and triethylamine (1.3 mL, 9.70 mmol) were added tocompound 23-2 (0.50 g, 3.28 mmol). Diphenylphosphoryl azide (1.3 mL,5.82 mmol) was added to the solution at room temperature, and themixture was stirred at 90° C. for 16 hours. The mixture was cooled toroom temperature, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane/ethylacetate=60/40→40/60) to obtain compound 23-3 (0.95 g, 73%).

¹H NMR (300 MHz, DMSO-d₆, δ): 8.97 (s, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.72(s, 1H), 6.54 (d, J=8.1 Hz, 1H), 6.30 (d, J=8.1 Hz, 1H), 4.60 (s, 2H),3.76 (s, 3H), 1.44 (s, 9H).

Step 4

tert-Butyl (5-methoxy-2H-chroman-3-yl)carbamate (Compound 23-4)

Compound 23-3 (0.95 g, 3.42 mmol) was dissolved in ethanol (20 mL), andpalladium/carbon (0.90 g) was added to the solution. The mixture wasstirred under hydrogen atmosphere at room temperature for 16 hours. Thereaction liquid was filtered with Celite®. The filtrate was concentratedunder reduced pressure to obtain compound 23-4 as a crude product, whichwas used as it is in the next reaction.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.04 (t, J=8.1 Hz, 1H), 6.96 (d, J=6.6 Hz,1H), 6.51 (d, J=8.1 Hz, 1H), 6.40 (d, J=8.1 Hz, 1H), 4.08-4.05 (m, 1H),3.82 (s, 3H), 3.59-3.82 (m, 2H), 2.80 (dd, J=16.8, 5.4 Hz, 1H),2.44-2.38 (m, 1H), 1.40 (s, 9H).

Step 5

3-Aminochroman-5-ol (Compound 23-5)

Pyridine hydrochloride (150 mg) was added to compound 23-4, and themixture was stirred at 150° C. for 30 minutes using a microwave reactor,Initiator, manufactured by Biotage. The mixture was cooled to roomtemperature, and a saturated aqueous sodium bicarbonate solution wasadded to the mixture. The organic layer was extracted withdichloromethane, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=40/60→30/70) to obtain compound23-5 (40.0 mg, 62% over two steps).

¹H NMR (300 MHz, DMSO-d₆, δ): 9.31 (s, 1H), 6.82 (t, J=8.1 Hz, 1H), 6.33(d, J=7.8 Hz, 1H), 6.20 (d, J=8.1 Hz, 1H), 4.01-3.98 (m, 1H), 3.48 (t,J=9.0 Hz, 1H), 3.05-3.02 (m, 1H), 2.78 (dd, J=16.8, 4.8 Hz, 1H),2.19-2.11 (m, 1H).

Step 6

5-(4-Chlorophenoxy)chroman-3-amine (Compound 23-6)

Compound 23-6 (0.110 g, 26%) was obtained in the same manner as step 4of example 4, using compound 23-5.

ESIMS m/z: [M+H]⁺ 276.

Step 7

N-{5-(4-Chlorophenoxy)chroman-3-yl}acrylamide (Compound 34)

Compound 34 (21 mg, 18%) was obtained in the same manner as step 5 ofexample 1, using compound 23-6.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.25 (d, J=6.6 Hz, 1H), 7.40 (d, J=9.0 Hz,2H), 7.14 (t, J=8.1 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.70 (d, J=8.1 Hz,1H), 6.50 (d, J=7.8 Hz, 1H), 6.26 (dd, J=17.1, 9.9 Hz, 1H), 6.10 (dd,J=17.1, 2.4 Hz, 1H), 5.59 (dd, J=9.9, 2.4 Hz, 1H), 4.21-4.13 (m, 2H),3.93-3.88 (m, 1H), 2.87 (dd, J=17.1, 5.7 Hz, 1H), 2.57-2.50 (m, 1H);ESIMS m/z: [M+H]⁺ 330.

The following compounds were synthesized in accordance with thesynthesis method of compound 34.

N-{6-(4-Chlorophenoxy)chroman-3-yl}acrylamide (Compound 36)

ESIMS m/z: [M+H]⁺ 330.

N-{7-(4-Chlorophenoxy)chroman-3-yl}acrylamide (Compound 37)

ESIMS m/z: [M+H]⁺ 330.

N-[7-{4-(Trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compound 38)

ESIMS m/z: [M+H]⁺ 364.

Example 24

Step 1

5-{4-(Trifluoromethyl)phenoxy}chroman-3-amine (Compound 24-1)

Compound 24-1 (0.13 g, 46%) was obtained in the same manner as step 4 ofexample 4, using compound 23-5.

ESIMS m/z: [M+H]⁺ 310.

Step 2

N-[5-{4-(Trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compound 35)

Compound 35 (70 mg, 46%) was obtained in the same manner as step 5 ofexample 1, using compound 24-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.26 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.8 Hz,2H), 7.20 (t, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.78-6.76 (m, 1H),6.64 (dd, J=8.0, 0.8 Hz, 1H), 6.24 (dd, J=17.2, 10.4 Hz, 1H), 6.09 (dd,J=16.8, 2.0 Hz, 1H), 5.59 (dd, J=10.0, 2.4 Hz, 1H), 4.20-4.15 (m, 2H),3.94-3.89 (m, 1H), 2.83 (dd, J=16.8, 6.4 Hz, 1H), 2.56-2.54 (m, 1H);

ESIMS m/z: [M+H]⁺ 364.

Step 3

N-[5-{4-(Trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compounds 65and 66)

Compound 35 was optically resolved under the following chiralpreparative conditions to obtain compound 65 (17 mg, 25%) having aretention time of 6.65 minutes and compound 66 (19 mg, 29%) having aretention time of 8.25 minutes.

-   Compound 65: ESIMS m/z: [M+H]⁺ 364.-   Compound 66: ESIMS m/z: [M+H]⁺ 364.    Chiral Preparative Conditions-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IA/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 95% carbon dioxide/5% isopropanol-   Preparative time: 15 minutes-   Flow rate: 30 mL/minute-   Retention time: 6.65 minutes (compound 65), 8.25 minutes (compound    66)

Example 25

Step 1

3-(2-Methoxyphenoxy)propionic acid (Compound 25-1)

DMF (10 mL) was added to sodium hydride (65% liquid paraffin dispersion,1.73 g, 48.38 mmol). A solution prepared by adding DMF (20 mL) to2-methoxyphenol (5.00 g, 40.32 mmol) was added dropwise to the mixtureunder nitrogen atmosphere at 0° C., and the mixture was stirred forminutes. A solution prepared by adding DMF (20 mL) to 3-bromopropionicacid (7.40 g, 48.38 mmol) was added dropwise to the mixture, and themixture was stirred under nitrogen atmosphere at room temperature for 18hours. Water was added to the mixture. The mixture was acidified by theaddition of a 2 mol/L aqueous hydrochloric acid solution (20 mL). Theorganic layer was extracted with ethyl acetate, dried over anhydroussodium sulfate, concentrated under reduced pressure to obtain compound25-1 as a crude product, which was used as it is in the next reaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 12.34 (br, 1H), 6.97-6.86 (m, 2H),6.76-6.73 (m, 1H), 4.13 (t, J=6.0 Hz, 2H), 3.73 (5, 3H), 2.68 (t, J=6.0Hz, 2H).

Step 2

8-Methoxychroman-4-one (Compound 25-2)

Trifluoromethanesulfonic acid (1 mL) was added to compound 25-1, and themixture was stirred at 80° C. for 30 minutes. A solution prepared byadding dichloromethane to the mixture left to cool to room temperaturewas slowly added to water. The organic layer was extracted withdichloromethane, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=100/0→70/30) to obtain compound25-2 (0.15 g, 13% over two steps).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.32-7.30 (m, 1H), 7.23-7.21 (m, 1H), 6.97(t, J=8.0 Hz, 1H), 4.53 (t, J=6.4 Hz, 2H), 3.79 (s, 3H), 2.77 (t, J=6.8Hz, 2H).

Step 3

8-Hydroxychroman-4-one (Compound 25-3)

Compound 25-2 (0.10 g, 0.56 mmol) was dissolved in dichloromethane (3mL), and the solution was cooled to −78° C. A 1 mol/L boron tribromidesolution in dichloromethane (2.80 mL, 2.80 mmol) was added dropwise tothe solution under nitrogen atmosphere, and the mixture was stirred atroom temperature for 2 hours. The mixture was cooled to −78° C., andwater was added to the mixture. The organic layer was extracted withethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain compound 25-3 as a crude product, whichwas used as it is in the next reaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 9.52 (s, 1H), 7.19 (dd, J=8.0, 1.6 Hz,1H), 7.04-7.02 (m, 1H), 6.84 (t, J=7.6 Hz, 1H), 4.53 (t, J=6.4 Hz, 2H),2.77 (t, J=6.4 Hz, 2H).

Step 4

8-(4-chlorophenoxy)chroman-4-one (Compound 25-4)

Compound 25-4 (0.10 g, 39% over two steps) was obtained in the samemanner as step 1 of example 3, using compound 25-3 and4-chlorophenylboronic acid.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.65 (dd, J=8.0, 1.2 Hz, 1H), 7.39-7.37(m, 3H), 7.08 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 4.53 (t, J=6.4Hz, 2H), 2.81 (t, J=6.4 Hz, 2H).

Step 5

8-(4-Chlorophenoxy)chroman-4-one oxime (Compound 25-5)

Compound 25-4 (0.10 g, 0.364 mmol) was dissolved in pyridine (2 mL), andhydroxylamine hydrochloride (0.05 g, 0.72 mmol) was added to thesolution. The mixture was stirred at 80° C. for 2 hours. The mixture wascooled to room temperature, and a 2 mol/L aqueous hydrochloric acidsolution (5 mL) was added to the mixture. The organic layer wasextracted with dichloromethane, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtained compound 25-5 as a crudeproduct, which was used as it is in the next reaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 11.39 (s, 1H), 7.69-7.67 (m, 1H), 7.35 (d,J=9.2 Hz, 2H), 7.08-7.06 (m, 1H), 7.00-6.96 (m, 1H), 6.89 (d, J=9.2 Hz,2H), 4.14 (t, J=6.0 Hz, 2H), 2.83 (t, J=6.0 Hz, 2H).

Step 6

8-(4-Chlorophenoxy)chroman-4-one O-tosyl oxime (Compound 25-6)

A solution prepared by adding THF (2 mL) to compound 25-5 (0.10 g, in0.34 mmol) was added dropwise to a suspension solution prepared byadding THF (1 mL) to sodium hydride (65% liquid paraffin dispersion,0.025 g, 0.69 mmol) under nitrogen atmosphere at room temperature, andthe mixture was stirred for 30 minutes. A solution prepared by addingTHF (2 mL) to p-toluenesulfonyl chloride (0.10 g, 0.519 mmol) was addeddropwise to the mixture. The mixture was stirred under nitrogenatmosphere at room temperature for one hour. Water was added to themixture. The organic layer was extracted with dichloromethane, driedover anhydrous sodium sulfate, and concentrated under reduced pressureto obtain compound 25-6 as a crude product, which was used as it is inthe next reaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.93 (d, J=8.0 Hz, 2H), 7.57-7.45 (m, 3H),7.34 (d, J=8.0 Hz, 2H), 7.24-7.22 (m, 1H), 7.06-7.00 (m, 1H), 6.89 (d,J=8.8 Hz, 2H), 4.18 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H), 2.43 (s,3H).

Step 7

3-Amino-8-(4-chlorophenoxy)chroman-4-one hydrochloride (Compound 25-7)

Compound 25-6 (0.10 g, 0.22 mmol) was dissolved in toluene (5 mL), and a24% potassium ethoxide solution in ethanol (0.11 mL, 0.338 mmol) wasadded to the solution. The mixture was stirred under argon atmosphere atroom temperature for 18 hours. tert-Butylmethyl ether (20 mL) was addedto the mixture, and the mixture was filtered with Celite®. Concentratedhydrochloric acid (0.2 mL) was added to the filtrate, and the mixturewas stirred at room temperature for one hour. The liquid mixture wasconcentrated under reduced pressure, and tert-butylmethyl ether wasadded to the residue for reslurrying to obtain compound 25-7 (0.02 g,14% over three steps).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (s, 3H), 7.70 (dd, J=7.6, 1.2 Hz,1H), 7.46 (dd, J=7.6, 1.2 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.19 (t,J=8.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.79-4.71 (m, 2H), 4.50-4.42 (m,1H).

Step 8

N-{8-(4-Chlorophenoxy)-4-oxochroman-3-yl}acrylamide (Compound 39)

Compound 39 (0.11 g, 52%) was obtained in the same manner as step 5 ofexample 1, using compound 25-7.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.58 (d, J=7.6 Hz, 1H), 7.68 (dd, J=7.6,1.2 Hz, 1H), 7.42-7.38 (m, 3H), 7.14 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.8Hz, 2H), 6.35 (dd, J=17.2, 10.4 Hz, 1H), 6.15 (dd, J=17.2, 1.6 Hz, 1H),5.69 (dd, J=10.0, 1.6 Hz, 1H), 5.02-4.96 (m, 1H), 4.55-4.51 (m, 1H),4.36-4.30 (m, 1H);

ESIMS m/z: [M+H]⁺ 344.

Example 26

Step 1

8-{4-(Trifluoromethyl)phenoxy}chroman-4-one (Compound 26-1)

Compound 26-1 (0.05 g, 27%) was obtained in the same manner as step 1 ofexample 3, using compound 25-3 and 4-(trifluoromethyl)phenylboronicacid.

¹H-NMR (400 MHz, H, CDCl₃) δ: 7.80 (dd, J=8.0, 1.2 Hz, 1H), 7.57 (d,J=8.4 Hz, 2H), 7.28-7.26 (m, 1H), 7.06-6.91 (m, 3H), 4.54 (t, J=6.4 Hz,2H), 2.85 (t, J=6.4 Hz, 2H).

Step 2

8-{4-(Trifluoromethyl)phenoxy}chroman-4-one oxime (Compound 26-2)

Compound 26-2 was obtained as a crude product in the same manner as step5 of example 25, using compound 26-1, and used as it is in the nextreaction.

¹H NMR (300 MHz, DMSO-d₆, δ): 11.43 (s, 1H), 7.74 (dd, J=7.8, 1.2 Hz,1H), 7.68 (d, J=8.7 Hz, 2H), 7.18 (dd, J=8.1, 1.5 Hz, 1H), 7.05-7.03 (m,3H), 4.14 (t, J=6.0 Hz, 2H), 2.83 (t, J=6.3 Hz, 2H).

Step 3

8-{4-(Trifluoromethyl)phenoxy}chroman-4-one O-tosyl oxime (Compound26-3)

Compound 26-3 was obtained as a crude product in the same manner as step6 of example 25, using compound 26-2, and used as it is in the nextreaction.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.94 (d, J=8.1 Hz, 2H), 7.80 (t, J=7.8 Hz,1H), 7.68-7.61 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.36-7.33 (m, 1H),7.10-7.01 (m, 3H), 4.18 (t, J=6.3 Hz, 2H), 3.01 (t, J=6.3 Hz, 2H), 2.43(s, 3H).

Step 4

3-Amino-8-{4-(trifluoromethyl)phenoxy}chroman-4-one hydrochloride(Compound 26-4)

Compound 26-4 (0.03 g, 31% over three steps) was obtained in the samemanner as step 7 of example 25, using compound 26-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.90 (s, 3H), 7.78-7.71 (m, 3H), 7.59 (d,J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 4.80-4.72(m, 2H), 4.52-4.46 (m, 1H).

Step 5

N-[4-Oxo-8-{4-(trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compound40)

Compound 40 (0.18 g, 69%) was obtained in the same manner as step 5 ofexample 1, using compound 26-4 (0.25 g, 0.70 mmol).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.58 (d, J=7.6 Hz, 1H), 7.75-7.70 (m, 3H),7.53-7.51 (m, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.35(dd, J=17.2, 10.0 Hz, 1H), 6.15 (dd, J=17.2, 1.6 Hz, 1H), 5.68 (dd,J=10.0, 1.2 Hz, 1H), 5.04-4.97 (m, 1H), 4.54-4.50 (m, 1H), 4.37-4.31 (m,1H);

ESIMS m/z: [M+H]⁺ 378.

Example 27

Step 1

5-Bromo-8-methoxy-2H-chromene-3-carbonitrile (Compound 27-1)

Compound 27-1 (0.12 g, 21%) was obtained in the same manner as step 1 ofexample 23, using commercially available6-bromo-2-hydroxy-3-methoxybenzaldehyde.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.53 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 7.05(d, J=8.7 Hz, 1H), 4.87 (d, J=1.2 Hz, 2H), 3.77 (s, 3H).

Step 2

5-Bromo-8-methoxy-2H-chromene-3-carboxylic acid (Compound 27-2)

Compound 27-2 (0.10 g, 85%) was obtained in the same manner as step 2 ofexample 23, using compound 27-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 13.18 (br, 1H), 7.45 (s, 1H), 7.20 (d,J=8.7 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 4.89 (d, J=1.2 Hz, 2H), 3.77 (s,3H).

Step 3

tert-Butyl (5-bromo-8-methoxy-2H-chromen-3-yl)carbamate (Compound 27-3)

Compound 27-3 (0.10 g, 80%) was obtained in the same manner as step 3 ofexample 23, using compound 27-2.

¹H-NMR (300 MHz, DMSO-d₆, δ): 9.22 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 6.77(s, 1H), 6.72 (d, J=8.7 Hz, 1H), 4.64 (s, 2H), 3.72 (s, 3H), 1.46 (s,9H).

Step 4

tert-Butyl (8-methoxy-5-methyl-2H-chromen-3-yl)carbamate (Compound 27-4)

Compound 27-3 (0.90 g, 2.52 mmol) was dissolved in 1,4-dioxane (20 mL),and trimethylboroxine (0.41 g, 5.05 mmol), potassium carbonate (0.69 g,5.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25mmol) were added to the solution. The mixture was stirred at 199° C. for16 hours. The liquid mixture was filtered, and water was added to thefiltrate. The organic layer was extracted with tert-butyl methyl ether,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=60/40→50/50) to obtain compound 27-4 (0.65 g,88%).

¹H NMR (300 MHz, DMSO-d₆, δ): 9.06 (s, 1H), 6.64-6.61 (m, 3H), 4.58 (s,2H), 3.68 (s, 3H), 2.12 (s, 3H), 1.45 (s, 9H).

Step 5

tert-Butyl (8-methoxy-5-methyl-2H-chroman-3-yl)carbamate (Compound 27-5)

Compound 27-5 was obtained as a crude product in the same manner as step4 of example 23, using compound 27-4, and used as it is in the nextreaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 6.97 (d, J=6.80 Hz, 1H), 6.66 (q, J=8.4Hz, 2H), 4.06 (d, J=9.6 Hz, 1H), 3.80-3.61 (m, 5H), 2.79 (dd, J=16.4,5.6 Hz, 1H), 2.46-2.44 (m, 1H), 2.06 (s, 3H), 1.40 (s, 9H).

Step 6

3-Amino-5-methylchroman-8-ol hydrobromide (Compound 27-6)

Compound 27-5 was dissolved in dichloromethane (10 mL), and the solutionwas cooled to 0° C. A 1 mol/L boron tribromide solution indichloromethane (8.5 mL, 8.53 mmol) was added dropwise to the solutionunder nitrogen atmosphere, and the mixture was stirred at roomtemperature for 2 hours. The mixture was cooled to 0° C., and methanol(15 mL) was added to the mixture. The mixture was concentrated underreduced pressure, and tert-butyl methyl ether was added to the residuefor reslurrying to obtain compound 27-6 (0.38 g, 62% over three steps).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (br, 1H), 8.14 (br, 3H), 6.59 (q,J=8.0 Hz, 2H), 4.11 (s, 2H), 3.81 (br, 1H), 2.99 (dd, J=17.2, 5.6 Hz,1H), 2.63-2.58 (m, 1H), 2.05 (s, 3H).

Step 7

8-(4-Chlorophenoxy)-5-methylchroman-3-amine (Compound 27-7)

Compound 27-7 (0.150 g, 39%) was obtained in the same manner as step 4of example 4, using compound 27-6.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.31 (d, J=9.0 Hz, 2H), 6.85-6.76 (m, 4H),4.00-3.98 (m, 1H), 3.59-3.47 (m, 2H), 2.72 (br, 1H), 2.27-2.25 (m, 1H),2.17 (s, 3H).

Step 8

N-{8-(4-Chlorophenoxy)-5-methylchroman-3-yl}acrylamide (Compound 41)

Compound 41 (0.18 g, 26%) was obtained in the same manner as step 5 ofexample 1, using compound 27-7.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.28 (d, J=6.6 Hz, 1H), 7.31 (d, J=9.0 Hz,2H), 6.91-6.78 (m, 4H), 6.28 (dd, J=17.1, 10.2 Hz, 1H), 6.11 (dd,J=17.1, 2.1 Hz, 1H), 5.60 (dd, J=9.9, 2.4 Hz, 1H), 4.24-4.20 (m, 1H),4.04-3.99 (m, 1H), 3.86-3.80 (m, 1H), 3.00-2.93 (m, 1H), 2.64-2.56 (m,1H), 2.18 (s, 3H);

ESIMS m/z: [M+H]⁺ 344.

Example 28

Step 1

8-Methoxychroman-3-amine (Compound 28-1)

Compound 28-1 was obtained as a crude product in the same manner as step4 of example 1, using commercially available 8-methoxychroman-3-one, andwas used as it is in the next reaction.

¹H NMR (300 MHz, DMSO-d₆, δ): 6.74 (br, 2H), 6.62-6.61 (m, 1H),4.09-4.03 (m, 1H), 3.66 (s, 3H), 3.79-3.66 (m, 1H), 3.08-3.06 (m, 1H),2.96-2.83 (m, 1H), 2.61-2.41 (m, 1H).

Step 2

3-Aminochroman-8-ol hydrobromide (Compound 28-2)

Compound 28-2 (0.25 g, 30% over two steps) was obtained in the samemanner as step 6 of example 27, using compound 28-1.

ESIMS m/z: [M+H]⁺ 166.

Step 3

8-(4-Chlorophenoxy)chroman-3-amine (Compound 28-3)

Compound 28-3 (0.150 g, 36%) was obtained in the same manner as step 4of example 4, using compound 28-2.

ESIMS m/z: [M+H]⁺ 276.

Step 4

N-{8-(4-Chlorophenoxy)chroman-3-yl}acrylamide (Compound 42)

Compound 42 (35 mg, 19%) was obtained in the same manner as step 5 ofexample 1, using compound 28-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.29 (d, J=6.9 Hz, 1H), 7.33 (d, J=8.7 Hz,2H), 7.03-7.01 (m, 1H), 6.91-6.86 (m, 4H), 6.29 (dd, J=17.1, 10.2 Hz,1H), 6.10 (dd, J=16.8, 2.1 Hz, 1H), 5.60 (dd, J=10.2, 2.4 Hz, 1H),4.21-4.17 (m, 1H), 4.09-4.05 (m, 1H), 3.92-3.86 (m, 1H), 3.15-309 (m,1H), 2.82-2.74 (m, 1H);

ESIMS m/z: [M+H]⁺ 330.

The following compounds were synthesized in accordance with thesynthesis method of compound 42.

N-[8-{3-(Trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compound 43)

ESIMS m/z: [M−H]⁺ 362.

N-[8-{4-(Trifluoromethoxy)phenoxy}chroman-3-yl]acrylamide (Compound 45)

ESIMS m/z: [M−H]⁺ 378.

N-{8-(3,4-Dichlorophenoxy)chroman-3-yl}acrylamide (Compound 46)

ESIMS m/z: [M−H]⁺ 362, 364.

N-[8-{4-Chloro-3-(trifluoromethyl)phenoxy}chroman-3-yl]acrylamide(Compound 47)

ESIMS m/z: [M−H]⁺ 396.

N-[8-{(5-Chloropyridin-2-yl)oxy}chroman-3-yl]acrylamide (Compound 48)

ESIMS m/z: [M+H]⁺ 331.

N-[8-{(6-Chloropyridin-3-yl)oxy}chroman-3-yl]acrylamide (Compound 49)

ESIMS m/z: [M+H]⁺ 331.

N-[8-{(4,5-Dichloropyridin-2-yl)oxy}chroman-3-yl]acrylamide (Compound52)

ESIMS m/z: [M+H]⁺ 365, 367.

N-[8-{(5,6-Dichloropyridin-2-yl)oxy}chroman-3-yl]acrylamide (Compound53)

ESIMS m/z: [M+H]⁺ 365, 367.

N-[8-{(5-Chloro-6-methylpyridin-2-yl)oxy}chroman-3-yl]acrylamide(Compound 54)

ESIMS m/z: [M+H]⁺ 345.

N-[8-{(5-Chloro-4-methylpyridin-2-yl)oxy}chroman-3-yl]acrylamide(Compound 55)

ESIMS m/z: [M+H]⁺ 345.

N-(8-[{6-Chloro-5-(trifluoromethyl)pyridin-2-yl}oxy]chroman-3-yl)acrylamide(Compound 57)

ESIMS m/z: [M+H]⁺ 399.

N-(8-[{4,5-Bis(trifluoromethyl)pyridin-2-yl}oxy]chroman-3-yl)acrylamide(Compound 58)

ESIMS m/z: [M+H]⁺ 433.

N-[8-{(6-Isopropoxypyridin-3-yl)oxy}chroman-3-yl]acrylamide (Compound154)

ESIMS m/z: [M+H]⁺ 355.

Step 5

N-{8-(4-chlorophenoxy)chroman-3-yl}acrylamide (Compounds 59 and 60)

Compound 42 was optically resolved under the following chiralpreparative conditions to obtain compound 59 (63 mg, 31%) having aretention time of 148 minutes and compound 60 (68 mg, 33%) having aretention time of 4.57 minutes.

-   Compound 59: ESIMS m/z: [M+H]⁺ 330.-   Compound 60: ESIMS m/z: [M+H]⁺ 330.    Chiral Preparative Conditions-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IB/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 90% carbon dioxide/10% methanol-   Preparative time: 6 minutes-   Flow rate: 30 mL/minute-   Retention time: 3.48 minutes (compound 59), 4.57 minutes (compound    60)

Example 29

Step 1

8-{4-(trifluoromethyl)phenoxy}chroman-3-amine (Compound 29-1)

Compound 29-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2, and used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 310.

Step 2

N-[8-{4-(Trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compound 44)

Compound 44 (0.17 g, 33% over two steps) was obtained in the same manneras step 5 of example 1, using compound 29-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.28 (d, J=6.8 Hz, 1H), 7.65 (d, J=8.8 Hz,2H), 7.08-6.92 (m, 5H), 6.28 (dd, J=17.2, 10.4 Hz, 1H), 6.10 (d, J=17.2,2.0 Hz, 1H), 5.60 (dd, J=10.0, 2.0 Hz, 1H), 4.21-4.19 (m, 1H), 4.08-4.05(m, 1H), 3.91-3.87 (m, 1H), 3.17-3.10 (m, 1H), 2.83-2.77 (m, 1H)

ESIMS m/z: [M+H]⁺ 364.

Step 3

N-[8-{4-(Trifluoromethyl)phenoxy}chroman-3-yl]acrylamide (Compounds 61and 62)

Compound 44 was optically resolved under the following chiralpreparative conditions to obtain compound 61 (46 mg, 34%) having aretention time of 4.17 minutes and compound 62 (66 mg, 48%) having aretention time of 5.74 minutes.

-   Compound 61: ESIMS m/z: [M+H]⁺ 364.-   Compound 62: ESIMS m/z: [M+H]⁺ 364.    Chiral Preparative Conditions-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IB/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 93% carbon dioxide/3.5% methanol/3.5%    chloroform-   Preparative time: 10 minutes-   Flow rate: 30 mL/minute-   Retention time: 4.17 minutes (Compound 61), 5.74 minutes (Compound    62)

Example 30

Step 1

8-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]chroman-3-amine (Compound 30-1)

Compound 30-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available2-chloro-5-(trifluoromethyl)pyridine, and used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 311.

Step 2

N-(8-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]chroman-3-yl)acrylamide(Compound 50)

Compound 50 (82.0 mg, 55% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 30-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.35 (br, 1H), 7.90 (dd, J=8.6, 2.5 Hz, 1H),7.06 (d, J=8.6 Hz, 1H), 7.00-6.95 (m, 3H), 6.27 (dd, J=17.0, 1.6 Hz,1H), 6.25-6.22 (m, 1H), 6.05 (dd, J=17.0, 10.2 Hz, 1H), 5.63 (dd,J=10.2, 1.6 Hz, 1H), 4.59-4.54 (m, 1H), 4.12 (ddd, J=10.9, 2.0, 1.0 Hz,1H), 4.05 (dd, J=10.9, 2.0 Hz, 1H), 3.19 (dd, J=17.0, 5.2 Hz, 1H),2.87-2.85 (m, 1H);

ESIMS m/z: [M+H]⁺ 365.

Step 3

N-(8-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]chroman-3-yl)acrylamide(Compounds 63 and 64)

Compound 50 was optically resolved under the following chiralpreparative conditions to obtain compound 63 (23 mg, 34%) having aretention time of 5.95 minutes and compound 64 (26 mg, 38%) having aretention time of 7.82 minutes.

-   Compound 63: ESIMS m/z: [M+H]⁺ 365.-   Compound 64: ESIMS m/z: [M+H]⁺ 365.    Chiral Preparative Conditions-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IA/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 93% carbon dioxide/7% isopropanol-   Preparative time: 12 minutes-   Flow rate: 30 mL/minute-   Retention time: 5.95 minutes (Compound 63), 7.82 minutes (Compound    64)

Example 31

Step 1

8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]chroman-3-amine (Compound 31-1)

Compound 31-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available5-bromo-2-(trifluoromethyl)pyridine, and was used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 311.

Step 2

N-(8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]chroman-3-yl)acrylamide(Compound 51)

Compound 51 (43.4 mg, 29% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 31-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.39 (d, J=2.7 Hz, 1H), 7.60 (d, J=8.6 Hz,1H), 7.27 (dd, J=8.6, 2.7 Hz, 1H), 7.01-6.92 (m, 3H), 6.29 (dd, J=16.8,1.4 Hz, 1H), 6.12 (d, J=8.2 Hz, 1H), 6.07 (dd, J=16.8, 10.4 Hz, 1H),5.66 (dd, J=10.4, 1.4 Hz, 1H), 4.59-4.53 (m, 1H), 4.16 (ddd, J=11.1,2.0, 1.0 Hz, 1H), 4.10 (dd, J=11.1, 2.0 Hz, 1H), 3.20 (dd, J=17.0, 5.4Hz, 1H), 2.90 (dd, J=17.0, 2.0 Hz, 1H);

ESIMS m/z: [M+H]⁺ 365.

Example 32

Step 1

8-{(6-Chloro-5-methylpyridin-3-yl)oxy}chroman-3-amine (Compound 32-1)

Compound 32-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available2-chloro-5-iodo-3-methylpyridine, and used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 290.

Step 2

N-[8-{(6-Chloro-5-methylpyridin-3-yl)oxy}chroman-3-yl]acrylamide(Compound 56)

Compound 56 (2.7 mg, 7%) was obtained in the same manner as step 5 ofexample 1, using compound 32-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.92 (d, J=3.2 Hz, 1H), 7.17 (d, J=3.2 Hz,1H), 6.94-6.89 (m, 3H), 6.31 (dd, J=17.0, 1.4 Hz, 1H), 6.05 (dd, J=17.0,10.2 Hz, 1H), 5.88 (d, J=8.2 Hz, 1H), 5.67 (dd, J=10.2, 1.1 Hz, 1H),4.61-4.58 (m, 1H), 4.23 (ddd, J=11.1, 2.0, 1.0 Hz, 1H), 4.12 (dd,J=11.1, 2.0 Hz, 1H), 3.20 (dd, J=17.0, 5.2 Hz, 1H), 2.90 (dt, J=17.0,2.5 Hz, 1H), 2.36 (s, 3H);

ESIMS m/z: [M+H]⁺ 345.

Example 33

Step 1

7′,8′-Dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinoline] (Compound 33-1)

In toluene (34 mL), 7,8-dihydroquinolin-5(6H)-one (0.50 g, 3.40 mmol)was dissolved. Ethylene glycol (0.38 mL, 6.79 mmol) andp-toluenesulfonic acid monohydrate (0.13 mg, 0.679 mmol) were added tothe solution. The mixture was refluxed overnight using a Dean-Starkapparatus. The mixture was left to cool to room temperature, andtriethylamine (0.14 mL) was added to the mixture. The mixture wasconcentrated under reduced pressure. The residue was purified byaminosilica gel column chromatography (heptane/ethylacetate=100/0→80/20) to obtain compound 33-1 (374 mg, 58%).

¹H NMR (400 MHz, CDCl₃, δ): 8.49 (dd, J=4.8, 1.8 Hz, 1H), 7.79 (dd,J=8.1, 1.8 Hz, 1H), 7.15 (ddt, J=8.1, 4.8, 0.7 Hz, 1H), 4.20-4.12 (m,4H), 2.98-2.96 (m, 2H), 2.08-1.95 (m, 4H); ESIMS m/z: [M+H]⁺ 192.

Step 2

7′,8′-Dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinoline]1′-oxide (Compound33-2)

Compound 33-1 (0.374 g, 1.95 mmol) was dissolved in dichloromethane (20mL), and m-chloroperoxybenzoic acid (674 mg, 2.93 mmol) was added to thesolution. The mixture was stirred at room temperature for one hour. Asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium thiosulfate solution were added to the mixture. The mixture wasfiltered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25mL), and the filtrate was concentrated under reduced pressure to obtaincompound 33-2 (415 mg) as a crude product.

ESIMS m/z: [M+H]⁺ 208.

Step 3

7′,8′-Dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinolin]-8′-ol (Compound33-3)

Compound 33-2 (415 mg) as a crude product was dissolved in ethyl acetate(15 mL), and triethylamine (0.84 mL, 6.01 mmol) was added to thesolution. Trifluoroacetic anhydride (0.57 mL, 4.01 mmol) dissolved inethyl acetate (5 mL) was added to the mixture at −78° C. After stirredat −78° C. for one hour, the mixture was stirred at room temperatureovernight. A saturated aqueous sodium bicarbonate solution was added tothe mixture. The mixture was filtered with Presep ((R); diatomaceousearth, granular type M, 4.5 g/25 mL), and the filtrate was concentratedunder reduced pressure. Ethanol (1.0 mL) and a 2 mol/L aqueous sodiumhydroxide solution (1.0 mL) were added to the residue, and the mixturewas stirred at room temperature for one hour. Water was added to themixture. The organic layer was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform/methanol=97/3→93/7) to obtain compound 33-3 (325 mg, 78%over two steps).

¹H NMR (400 MHz, CDCl₃, δ): 8.56 (dd, J=4.8, 1.8 Hz, 1H), 7.81 (dd,J=8.2, 1.8 Hz, 1H), 7.27 (dd, J=8.2, 4.8 Hz, 1H), 4.69 (dd, J=9.1, 5.4Hz, 1H), 4.25-4.06 (m, 4H), 3.98 (br, 1H), 2.39-2.36 (m, 1H), 2.22-2.19(m, 1H), 2.01-1.94 (m, 2H);

ESIMS m/z: [M+H]⁺ 208.

Step 4

8′-Phenoxy-7′,8′-dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinoline](Compound 33-4)

Compound 33-3 (36.0 mg, 0.174 mmol), triphenylphosphine (91.0 mg, 0.347mmol), and phenol (33.0 mg, 0.347 mmol) were dissolved in THF (0.7 mL),and diisopropyl azodicarboxylate (0.068 mL) was added to the solution.The mixture was stirred at room temperature overnight. The mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (heptane/ethyl acetate=80/20→50/50) to obtaincompound 33-4 (93.0 mg) as a crude product.

ESIMS m/z: [M+H]⁺ 284.

Step 5

8-Phenoxy-7,8-dihydroquinolin-5(6H)-one (Compound 33-5)

A 2 mol/L hydrochloric acid 1,4-dioxane solution (1 mL) was added tocompound 33-4 as a crude product, and the mixture was stirred at 50° C.overnight. The mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (heptane/ethylacetate=90/10→70/30) to obtain compound 33-5 (16.3 mg, 39% over twosteps).

¹H NMR (400 MHz, CDCl₃, δ): 8.80 (dd, J=4.8, 2.1 Hz, 1H), 8.35 (dd,J=7.9, 2.1 Hz, 1H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.32 (tt, J=7.9, 2.1Hz, 2H), 7.16-7.15 (m, 2H), 7.01 (td, J=7.9, 1.1 Hz, 1H), 5.63 (t, J=3.4Hz, 1H), 3.16-3.13 (m, 1H), 2.72-2.59 (m, 2H), 2.43-2.34 (m, 1H);

ESIMS m/z: [M+H]⁺ 240.

Step 6

8-Phenoxy-5,6,7,8-tetrahydroquinolin-5-amine (Compound 33-6)

Compound 33-6 (13.8 mg) was obtained as a crude product in the samemanner as step 4 of example 1, using compound 33-5 (15.0 mg, 0.063mmol).

ESIMS m/z: [M+H]⁺ 241.

Step 7

cis-N-(8-Phenoxy-5,6,7,8-tetrahydroquinolin-5-yl)acrylamide (Compound67)

Compound 33-6 (13.8 mg) as a crude product was dissolved indichloromethane (0.6 mL), and triethylamine (0.03 mL, 0.189 mmol) andacryloyl chloride (0.075 mL, 0.93 mmol) were added to the solution. Themixture was stirred at 0° C. for one hour. A saturated aqueous sodiumbicarbonate solution was added to the mixture. The mixture was filteredwith Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (heptane/ethylacetate=70/30→40/60) to obtain compound 67 (3.20 mg, 17% over twosteps).

¹H NMR (400 MHz, CDCl₃, δ): 8.58 (dt, J=4.5, 1.5 Hz, 1H), 7.71 (dd,J=8.2, 4.5 Hz, 1H), 7.31-7.27 (m, 3H), 7.10 (dd, J=8.6, 1.1 Hz, 2H),6.99 (tt, J=7.2, 1.1 Hz, 1H), 6.39 (dd, J=17.0, 1.4 Hz, 1H), 6.16 (dd,J=17.0, 10.2 Hz, 1H), 5.93 (d, J=9.1 Hz, 1H), 5.75 (dd, J=10.2, 1.4 Hz,1H), 5.45-5.38 (m, 2H), 2.44-2.42 (m, 1H), 2.18-1.98 (m, 3H);

ESIMS m/z: [M+H]⁺ 295.

Example 34

Step 1

8′-(3-Chlorophenoxy)-7′,8′-dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinoline](Compound 34-1)

Compound 34-1 (207 mg) was obtained as a crude product in the samemanner as step 4 of example 33, using compound 33-3 (80.0 mg, 0.386mmol) and 3-chlorophenol (99.0 mg, 0.772 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 8.64 (dd, J=4.8, 1.8 Hz, 1H), 7.88 (dd,J=7.9, 1.8 Hz, 1H), 7.33 (dd, J=7.9, 4.8 Hz, 1H), 7.21 (t, J=7.9 Hz,1H), 7.11 (t, J=2.3 Hz, 1H), 7.00-6.94 (m, 2H), 5.41 (t, J=3.4 Hz, 1H),4.23-4.14 (m, 4H), 2.35-2.30 (m, 3H), 2.00-1.97 (m, 1H); ESIMS m/z:[M+H]⁺ 318.

Step 2

8-(3-Chlorophenoxy)-7,8-dihydroquinolin-5(6H)-one (Compound 34-2)

Compound 34-2 (180 mg) was obtained as a crude product in the samemanner as step 5 of example 33, using compound 34-1 (207 mg) as a crudeproduct.

¹H NMR (400 MHz, CDCl₃, δ): 8.80 (dd, J=4.5, 1.8 Hz, 1H), 8.36 (dd,J=8.2, 1.8 Hz, 1H), 7.46 (dd, J=8.2, 4.5 Hz, 1H), 7.23 (t, J=8.2 Hz,1H), 7.19 (t, J=2.3 Hz, 1H), 7.07-7.05 (m, 1H), 7.00-6.98 (m, 1H), 5.60(t, J=3.9 Hz, 1H), 3.17-3.08 (m, 1H), 2.73-2.68 (m, 1H), 2.64-2.57 (m,1H), 2.45-2.37 (m, 1H);

ESIMS m/z: [M+H]⁺ 274.

Step 3

8-(3-Chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-amine (Compound 34-3)

Compound 34-3 (59.2 mg) was obtained as a crude product in the samemanner as step 6 of example 33, using compound 34-2 (180 mg) as a crudeproduct.

ESIMS m/z: [M+H]⁺ 275.

Step 4

cis-N-{8-(3-Chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 68)trans-N-{8-(3-Chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 79)

Compound 68 (26.8 mg, 38% in four stages) and compound 79 (5.50 mg, 8%in four stages) were obtained in the same manner as step 7 of example33, using compound 34-3 (59.2 mg) as a crude product. Compound 68: ¹HNMR (400 MHz, CDCl₃, δ): 8.59 (d, J=4.9 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H),7.30 (d, J=4.9 Hz, 1H), 7.23 (t, J=8.3 Hz, 1H), 7.12-7.11 (m, 1H),7.01-6.97 (m, 2H), 6.40 (dd, J=17.1, 1.5 Hz, 1H), 6.16 (dd, J=17.1, 10.2Hz, 1H), 5.82 (d, J=10.0 Hz, 1H), 5.76 (dd, J=10.2, 1.5 Hz, 1H),5.42-5.40 (m, 2H), 2.42-2.40 (m, 1H), 2.15-2.09 (m, 3H);

ESIMS m/z: [M+H]⁺ 329.

Compound 79: ¹H NMR (400 MHz, CDCl₃, δ): 8.62 (d, J=6.8 Hz, 1H), 7.74(d, J=6.8 Hz, 1H), 7.22-7.14 (m, 3H), 7.00-6.98 (m, 2H), 6.37 (dd,J=17.1, 1.9 Hz, 1H), 6.08 (dd, J=17.1, 10.2 Hz, 1H), 5.74-5.71 (m, 2H),5.46-5.44 (m, 2H), 2.45-2.42 (m, 1H), 2.27-2.18 (m, 2H), 1.96-1.90 (m,1H);

ESIMS m/z: [M+H]⁺ 329.

The following compounds were synthesized in accordance with thesynthesis method aforementioned.

cis-N-{8-(4-Chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 69)

ESIMS m/z: [M+H]⁺ 329.

trans-N-{8-(4-Chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 80)

ESIMS m/z: [M+H]⁺ 329.

cis-N-{2-Chloro-8-(3,4-dichlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 178)

ESIMS m/z: [M+H]⁺ 397.

Example 35

Step 1

2′-Chloro-7′,8′-dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinoline](Compound 35-1)

Commercially available 2-chloro-7,8-dihydroquinolin-5(6H)-one (1.50 g,8.26 mmol) was dissolved in toluene (83 mL). Ethylene glycol (0.92 mL,16.5 mmol) and pyridinium p-toluenesulfonate (208 mg, 0.826 mmol) wereadded to the solution. The mixture was refluxed for three hours using aDean-Stark apparatus during which ethylene glycol (0.92 mL, 16.5 mmol)was added four times every 30 minutes. The mixture was cooled to andtriethylamine (0.35 mL) was added to the mixture. The mixture wasconcentrated under reduced pressure. The residue was purified byaminosilica gel column chromatography (heptane/ethylacetate=90/10→70/30) to obtain compound 35-1 (1.75 g, 94%).

¹H NMR (400 MHz, CDCl₃, δ): 7.73 (d, J=8.2 Hz, 1H), 7.17 (d, J=8.2 Hz,1H), 4.21-4.08 (m, 4H), 2.93 (t, J=6.1 Hz, 2H), 2.03-1.93 (m, 4H);

ESIMS m/z: [M+H]⁺ 226.

Step 2

2′-Chloro-7′,8′-dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinolin]-8′-ol(Compound 35-2)

Compound 35-1 (2.35 g, 10.4 mmol) was dissolved in dichloromethane (104mL), and m-chloroperoxybenzoic acid (4.79 g, 20.8 mmol) was added to thesolution. After the mixture was stirred at room temperature overnight,m-chloroperoxybenzoic acid (2.39 g, 10.4 mmol) was further added to themixture. The mixture was stirred at room temperature for one hour. Themixture was basified by the addition of a 4 mol/L aqueous sodiumhydroxide solution, and a saturated aqueous sodium thiosulfate solutionwas added to the mixture. The organic layer was extracted withchloroform, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was dissolved in ethyl acetate (104 mL),and trifluoroacetic acid anhydride (0.57 mL, 4.01 mmol) was added to themixture at −78° C. The mixture was stirred at room temperatureovernight. The mixture was concentrated under reduced pressure. Ethanol(20 mL) and a 4 mol/L aqueous sodium hydroxide solution (2.0 mL) wereadded to the residue, and the mixture was stirred at room temperaturefor one hour. Water was added to the mixture. The organic layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (heptane/ethyl acetate=90/10→50/50) to obtaincompound 35-2 (1.63 g, 65%).

¹H NMR (400 MHz, CDCl₃, δ): 7.76 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz,1H), 4.67 (dd, J=8.6, 5.4 Hz, 1H), 4.16-4.12 (m, 4H), 2.38-2.31 (m, 1H),2.18 (ddd, J=13.4, 6.8, 2.5 Hz, 1H), 2.07-1.98 (m, 1H), 1.90 (ddd,J=14.0, 11.1, 2.3 Hz, 1H);

ESIMS m/z: [M+H]⁺ 242.

Step 3

2′-Chloro-8′-(4-chlorophenoxy)-7′,8′-dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinolin]-8′-ol(Compound35-3)

Compound 35-3 (68.5 mg) was obtained as a crude product in the samemanner as step 4 of example 33, using compound 35-2 (110 mg, 0.455 mmol)and 4-chlorophenol (117 mg, 9.10 mmol).

ESIMS m/z: [M+H]⁺ 352.

Step 4

2-Chloro-8-(4-chlorophenoxy)-7,8-dihydroquinolin-5(6H)-one (Compound35-4)

Compound 35-4 (57.5 mg, 41% over two steps) was obtained in the samemanner as step 5 of example 33, using compound 35-3 (422 mg) as a crudeproduct.

¹H NMR (400 MHz, CDCl₃, δ): 8.29 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.1 Hz,1H), 7.29-7.28 (m, 2H), 7.08 (td, J=6.1, 3.8 Hz, 2H), 5.49 (t, J=3.5 Hz,1H), 3.17-3.05 (m, 1H), 2.69-2.59 (m, 2H), 2.41-2.31 (m, 1H);

ESIMS m/z: [M+H]⁺ 308.

Step 5

2-Chloro-8-(4-chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-amine(Compound 35-5)

Compound 35-5 (23.5 mg) was obtained as a crude product in the samemanner as step 4 of example 1, using compound 35-4 (57.5 mg, 0.185mmol).

ESIMS m/z: [M+H]⁺ 309.

Step 6

cis-N-{2-Chloro-8-(4-chlorophenoxy)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 70)

Compound 70 (10.2 mg, 15% over two steps) was obtained in the samemanner as step 7 of example 33, using compound 35-5 (23.5 mg) as a crudeproduct.

¹H NMR (400 MHz, CDCl₃, δ): 7.66 (d, J=8.6 Hz, 1H), 7.27 (d, J=5.4 Hz,1H), 7.24 (t, J=2.9 Hz, 2H), 7.02 (td, J=6.2, 3.8 Hz, 2H), 6.39 (dd,J=16.8, 1.4 Hz, 1H), 6.16 (dd, J=16.8, 10.4 Hz, 1H), 5.95 (d, J=9.5 Hz,1H), 5.75 (dd, J=10.4, 1.4 Hz, 1H), 5.36-5.33 (m, 1H), 5.28-5.28 (m,1H), 2.42-2.33 (m, 1H), 2.08-2.01 (m, 3H);

ESIMS m/z: [M+H]⁺ 363.

The following compound was synthesized in accordance with the synthesismethod of compound 70.

cis-N-[2-Chloro-8-{(2-oxo-2H-chromen-7-yl)oxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 75)

ESIMS m/z: [M+H]⁺ 397.

Example 36

Step 1

8-(4-Chlorophenoxy)-2-methoxy-7,8-dihydroquinolin-5(6H)-one (Compound364)

Compound 35-4 (50 mg, 0.162 mmol) was dissolved in methanol (0.5 mL),and a 28% sodium methoxide solution in methanol (1 mL) was added to thesolution. The mixture was subjected to a reaction at a temperature of120° C. for 3 minutes, using a microwave reactor manufactured byBiotage. The mixture was concentrated under reduced pressure, and waterwas added to the residue. The mixture was filtered with Presep ((R);diatomaceous earth, granular type M, 4.5 g/25 mL). The filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (heptane/ethyl acetate=90/10→50/50) to obtaincompound 36-1 (39 mg, 79%).

¹H NMR (400 MHz, CDCl₃, δ): 8.20 (d, J=8.6 Hz, 1H), 7.25 (td, J=6.1, 3.6Hz, 2H), 7.13 (td, J=6.1, 3.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 1H), 5.42 (dd,J=4.5, 3.6 Hz, 1H), 3.90 (s, 3H), 3.08-3.03 (m, 1H), 2.66-2.61 (m, 1H),2.56-2.49 (m, 1H), 2.44-2.36 (m, 1H);

ESIMS m/z: [M+H]⁺ 304.

Step 2

8-(4-Chlorophenoxy)-2-methoxy-5,6,7,8-tetrahydroquinolin-5-amine(Compound 36-2)

Compound 36-2 was obtained as a crude product in the same manner as step4 of example 1, using compound 36-1 (39 mg, 0.128 mmol).

ESIMS m/z: [M+H]⁺ 305.

Step 3

cis-N-{8-(4-Chlorophenoxy)-2-methoxy-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 71)trans-N-{8-(4-Chlorophenoxy)-2-methoxy-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 81)

Compound 71 (9.2 mg, 20% over two steps) and compound 81 (1.8 mg, 4%over two steps) were obtained in the same manner as step 7 of example33, using compound 36-2 as a crude product. Compound 71: ¹H NMR (400MHz, CDCl₃, δ): 7.55 (d, J=8.6 Hz, 1H), 7.24-7.23 (m, 2H), 7.14 (td,J=6.2, 3.8 Hz, 2H), 6.70 (d, J=8.6 Hz, 1H), 6.36 (dd, J=17.2, 1.4 Hz,1H), 6.12 (dd, J=17.2, 10.4 Hz, 1H), 5.74 (d, J=9.5 Hz, 1H), 5.72 (dd,J=10.4, 1.4 Hz, 1H), 5.31-5.29 (m, 1H), 5.23-5.22 (m, 1H), 3.82 (s, 3H),2.32-2.28 (m, 1H), 2.18-2.01 (m, 3H);

ESIMS m/z: [M+H]⁺ 359.

Compound 81: ¹H NMR (400 MHz, CDCl₃, δ): 7.55 (d, J=8.6 Hz, 1H),7.24-7.23 (m, 2H), 7.12 (td, J=6.1, 3.9 Hz, 2H), 6.70 (d, J=8.6 Hz, 1H),6.34 (dd, J=16.8, 1.4 Hz, 1H), 6.06 (dd, J=16.8, 10.4 Hz, 1H), 5.69 (dd,J=10.4, 1.4 Hz, 1H), 5.63 (d, J=8.2 Hz, 1H), 5.34-5.32 (m, 1H),5.26-5.24 (m, 1H), 3.79 (s, 3H), 2.48-2.38 (m, 1H), 2.26-2.08 (m, 2H),1.95-1.88 (m, 1H);

ESIMS m/z: [M+H]⁺ 359.

The following compounds were synthesized in accordance with thesynthesis method of compound 71.

cis-N-{8-(4-Chlorophenoxy)-2-(dimethylamino)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 72)

ESIMS m/z: [M+H]⁺ 372.

cis-N-{8-(4-Chlorophenoxy)-2-(3,3-difluoroazetidin-1-yl)-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 73)

ESIMS m/z: [M+H]⁺ 420.

cis-N-{8-(4-Chlorophenoxy)-2-morpholino-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 74)

ESIMS m/z: [M+H]⁺ 414.

cis-N-{2-(Dimethylamino)-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]-5,6,7,8-tetrahydroquinolin-5-yl}acrylamide(Compound 78)

ESIMS m/z: [M+H]⁺ 407.

Example 37

Step 1

2′-Chloro-8′-{4-(trifluoromethyl)phenoxy}-7′,8′-dihydro-6′H-spiro[[1,3]dioxolane-2,5′-quinoline](Compound 37-1)

Compound 37-1 was obtained as a crude product in the same manner as step4 of example 33, using compound 35-2 (250 mg, 1.03 mmol) and4-(trifluoromethyl)phenol (335 mg, 2.07 mmol).

ESIMS m/z: [M+H]⁺ 386.

Step 2

2-Chloro-8-{4-(trifluoromethyl)phenoxy}-7,8-dihydroquinolin-5(6H)-one(Compound 37-2)

Compound 37-2 was obtained as a crude product in the same manner as step5 of example 33, using compound 37-1 (339 mg) as a crude product.

ESIMS m/z: [M+H]⁺ 342.

Step 3

2-Chloro-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-amine(Compound 37-3)

Compound 37-3 was obtained as a crude product in the same manner as step2 of example 3, using compound 37-2 (70 mg) as a crude product.

ESIMS m/z: [M+H]⁺ 343.

Step 4

cis-N-[2-Chloro-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 76)trans-N-[2-Chloro-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 82)

Compound 76 (33.7 mg, 52% in four stages) and compound 82 (21.6 mg, 33%in four stages) were obtained in the same manner as step 3 of example17, using compound 37-3 as a crude product. Compound 76: ¹H NMR (400MHz, CDCl₃, δ): 7.70 (d, J=8.5 Hz, 1H), 7.57 (dt, J=9.3, 2.4 Hz, 2H),7.31 (d, J=8.5 Hz, 1H), 7.17 (dt, J=9.3, 2.4 Hz, 2H), 6.41 (dd, J=17.1,1.3 Hz, 1H), 6.16 (dd, J=17.1, 10.3 Hz, 1H), 5.82 (d, J=9.4 Hz, 1H),5.77 (dd, J=10.3, 1.3 Hz, 1H), 5.41-5.38 (m, 2H), 2.43-2.41 (m, 1H),2.20-2.00 (m, 3H);

ESIMS m/z: [M+H]⁺ 397.

Compound 82: ¹H NMR (400 MHz, CDCl₃, δ): 7.73 (d, J=8.5 Hz, 1H), 7.57(d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 6.37(dd, J=16.6, 1.3 Hz, 1H), 6.08 (dd, J=16.6, 10.5 Hz, 1H), 5.73 (dd,J=10.5, 1.3 Hz, 1H), 5.72 (d, J=9.0 Hz, 1H), 5.45-5.42 (m, 2H),2.47-2.42 (m, 1H), 2.31-2.28 (m, 1H), 2.19-2.10 (m, 1H), 1.94-1.90 (m,1H);

ESIMS m/z: [M+H]⁺ 397.

The following compound was synthesized in accordance with the synthesismethod of compound 76.

cis-N-(2-Chloro-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]-5,6,7,8-tetrahydroquinolin-5-yl)acrylamide(Compound 77)

ESIMS m/z: [M+H]⁺ 398.

Example 38

Step 1

6-(4-Chlorophenoxy)pyridin-2-amine (Compound 384)

2-Amino-6-chloropyridine (100 mg, 0.778 mmol) was dissolved in DMF (4.00mL), and 4-chlorophenol (150 mg, 1.17 mmol) and cesium carbonate (507mg, 1.56 mmol) were added to the solution. The mixture was heated to180° C. and stirred for one hour using a microwave reactor, Initiator,manufactured by Biotage. A saturated aqueous sodium bicarbonate solutionwas added to the mixture. The organic layer was extracted with ethylacetate, washed with saturated saline, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified using a preparative HPLC [Waters Xbridge Prep C18 OBD column, 5μm silica, diameter 19 mm, length 100 mm; acetonitrile/0.05% aqueous TFAsolution (30/70→40/60)] to obtain compound 38-1 (92.0 mg, 54%).

¹H NMR (400 MHz, CDCl₃, δ): 7.41 (t, J=8.2 Hz, 1H), 7.34-7.29 (m, 2H),7.08-7.02 (m, 2H), 6.20 (d, J=8.2 Hz, 1H), 6.13 (d, J=8.2 Hz, 1H), 4.35(br, 2H);

ESIMS m/z: [M+H]⁺ 221.

Step 2

N-{6-(4-Chlorophenoxy)pyridin-2-yl}acrylamide (Compound 83)

Compound 38-1 (47.0 mg, 0.213 mmol) was dissolved in dichloromethane(2.00 mL), and triethylamine (0.0890 mL, 0.639 mmol) and acryloylchloride (0.0270 mL, 0.320 mmol) were added to the solution under icecooling. The mixture was stirred at room temperature for 1.5 hours.Water and ethyl acetate were added to the mixture. The mixture wasfiltered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25mL), and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (heptane/ethylacetate=100/0→60/40) to obtain compound 83 (34.0 mg, 58%).

¹H NMR (400 MHz, CDCl₃, δ): 7.99 (d, J=7.7 Hz, 1H), 7.76-7.65 (m, 2H),7.38-7.32 (m, 2H), 7.09-7.02 (m, 2H), 6.63 (d, J=7.7 Hz, 1H), 6.43 (dd,J=16.8, 1.1 Hz, 1H), 6.18 (dd, J=16.8, 10.2 Hz, 1H), 5.79 (dd, J=10.2,1.1 Hz, 1H);

ESIMS m/z: [M+H]⁺ 275.

The following compounds were synthesized in accordance with thesynthesis method of compound 83.

N-{2-(4-Chlorophenoxy)pyridin-4-yl}acrylamide (Compound 85)

ESIMS m/z: [M+H]⁺ 275.

N-{6-(4-Chlorophenoxy)-5-methylpyridin-2-yl}acrylamide (Compound 86)

ESIMS m/z: [M+H]⁺ 289.

N-{6-(4-Chlorophenoxy)-4-methylpyridin-2-yl}acrylamide (Compound 87)

ESIMS m/z: [M+H]⁺ 289.

N-{4-(4-Chlorophenoxy)-6-methylpyridin-2-yl}acrylamide (Compound 88)

ESIMS m/z: [M+H]⁺ 289.

N-{4-(4-Chlorophenoxy)-5-methylpyridin-2-yl}acrylamide (Compound 89)

ESIMS m/z: [M+H]⁺ 289.

N-{2-(4-Chlorophenoxy)-6-methylpyridin-4-yl}acrylamide (Compound 91)

ESIMS m/z: [M+H]⁺ 289.

N-{5-(4-Chlorophenoxy)-6-methylpyridin-3-yl}acrylamide (Compound 92)

ESIMS m/z: [M+H]⁺ 289.

N-{5-(4-Chlorophenoxy)-2-methylpyridin-3-yl}acrylamide (Compound 93)

ESIMS m/z: [M+H]⁺ 289.

N-{5-(4-chlorophenoxy)pyridin-3-yl}acrylamide (Compound 94)

ESIMS m/z: [M+H]⁺ 275.

Example 39 N-{4-(4-Chlorophenoxy)pyridin-2-yl}acrylamide (Compound 84)

Step 1

4-(4-Chlorophenoxy)pyridin-2-amine (Compound 39-1)

Compound 39-1 (38.0 mg, 44%) was obtained in the same manner as step 1of example 38, using 2-amino-4-chloropyridine.

¹H NMR (400 MHz, CDCl₃, δ): 7.95 (d, J=5.9 Hz, 1H), 7.39-7.33 (m, 2H),7.05-6.99 (m, 2H), 6.27 (dd, J=5.9, 2.3 Hz, 1H), 5.95 (d, J=2.3 Hz, 1H),4.39 (br, 2H);

ESIMS m/z: [M+H]⁺ 221.

Step 2

Compound 84 (18.0 mg, 38%) was obtained in the same manner as step 2 ofexample 38, using compound 39-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.14 (d, J=5.9 Hz, 1H), 8.01 (br, 1H), 7.90(d, J=2.3 Hz, 1H), 7.41-7.36 (m, 2H), 7.09-7.03 (m, 2H), 6.62 (dd, J=2.3Hz, 1H), 6.43 (dd, J=17.0, 1.1 Hz, 1H), 6.22 (dd, J=16.8, 10.4 Hz, 1H),5.81 (dd, J=10.4, 1.1 Hz, 1H);

ESIMS m/z: [M+H]⁺ 275.

Example 40 (E)-N-{4-(4-Chlorophenoxy)pyridin-2-yl}-2-butenamide(Compound 90)

Compound 90 (16.0 mg, 25%) was obtained in the same manner as step 2 ofexample 38, using compound 39-1 and (E)-2-butenoyl chloride.

¹H NMR (400 MHz, CDCl₃, δ): 8.12 (d, J=5.4 Hz, 1H), 7.88 (d, J=2.3 Hz,1H), 7.82 (br, 1H), 7.40-7.36 (m, 2H), 7.08-6.95 (m, 3H), 6.60 (dd,J=2.3 Hz, 1H), 5.91 (dd, J=15.0, 1.6 Hz, 1H), 1.92 (dd, J=7.0, 1.6 Hz,3H);

ESIMS m/z: [M+H]⁺ 289.

Example 41

Step 1

5-(3-(Trifluoromethyl)phenoxy)pyridin-3-amine (Compound 41-1)

In DMSO (2.00 mL), 3-iodobenzotrifluoride (0.0530 mL, 0.357 mmol) wasdissolved, and copper(I) iodide (3.40 mg, 0.0180 mmol), picolinic acid(4.39 mg, 0.0360 mmol), tripotassium phosphate (151 mg, 0.713 mmol), and3-amino-5-hydroxypyridine (47.0 mg, 0.428 mmol) were added to thesolution. The mixture was stirred at 80° C. for 4 hours. A saturatedaqueous sodium bicarbonate solution was added to the mixture. Theorganic layer was extracted with ethyl acetate, washed with saturatedsaline, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified using a preparative HPLC[Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length100 mm; acetonitrile/0.05% aqueous TFA solution (30/70→40/60)] to obtaincompound 41-1 (36.0 mg, 40%).

¹H NMR (400 MHz, CDCl₃, δ): 7.92 (s, 1H), 7.82 (s, 1H), 7.51-7.35 (m,2H), 7.30-7.16 (m, 2H), 6.63 (s, 1H), 3.79 (br, 2H)

ESIMS m/z: [M+H]⁺ 255.

Step 2

N-[5-{3-(Trifluoromethyl)phenoxy}pyridin-3-yl)acrylamide (Compound 95)

Compound 95 (26.0 mg, 60%) was obtained in the same manner as step 2 ofexample 38, using compound 41-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H),7.56-7.17 (m, 5H), 6.46 (d, J=16.8 Hz, 1H), 6.25 (dd, J=16.8, 10.0 Hz,1H), 5.85 (d, J=10.0 Hz, 1H);

ESIMS m/z: [M+H]⁺ 309.

Example 42

Step 1

5-(4-(Trifluoromethyl)phenoxy)pyridin-3-amine (Compound 42-1)

Compound 42-1 (30.0 mg, 33%) was obtained in the same manner as step 1of example 41, using 4-iodobenzotrifluoride.

¹H NMR (400 MHz, CDCl₃, δ): 7.93 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.3 Hz,1H), 7.60 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 6.65 (t, J=2.3 Hz,1H), 3.79 (br, 2H);

ESIMS m/z: [M+H]⁺ 255.

Step 2

N-[5-{4-(Trifluoromethyl)phenoxy}pyridin-3-yl]acrylamide (Compound 96)

Compound 96 (24.0 mg, 66%) was obtained in the same manner as step 2 ofexample 38, using compound 42-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.55 (br, 1H), 8.64 (d, J=2.3 Hz, 1H),8.21 (d, J=2.3 Hz, 1H), 7.94 (t, J=2.3 Hz, 1H), 7.80 (d, J=8.6 Hz, 2H),7.28 (d, J=8.6 Hz, 2H), 6.41 (dd, J=16.8, 10.0 Hz, 1H), 6.28 (dd,J=16.8, 1.8 Hz, 1H), 5.82 (dd, J=10.0, 1.8 Hz, 1H); ESIMS m/z: [M+H]⁺309.

Example 43

Step 1

5-(4-(Trifluoromethoxy)phenoxy)pyridin-3-amine (Compound 43-1)

Compound 43-1 (33.0 mg, 36%) was obtained in the same manner as step 1of example 41, using 1-iodo-4-(trifiuoromethoxy)benzene.

¹H-NMR (400 MHz, CDCl₃, δ): 7.88 (d, J=2.3 Hz, 1H), 7.80 (d, J=2.3 Hz,1H), 7.24-7.17 (m, 2H), 7.06-7.00 (m, 2H), 6.59 (t, J=2.3 Hz, 1H), 3.75(br, 2H);

ESIMS m/z: [M+H]⁺ 271.

Step 2

N-[5-{4-(Trifluoromethoxy)phenoxy}pyridin-3-yl]acrylamide (Compound 100)

Compound 100 (26.0 mg, 66%) was obtained in the same manner as step 2 ofexample 38, using compound 43-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.50 (br, 1H), 8.61 (d, J=2.3 Hz, 1H),8.15 (d, J=2.3 Hz, 1H), 7.84 (t, J=2.3 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H),7.24 (d, J=8.6 Hz, 2H), 6.40 (dd, J=16.8, 10.0 Hz, 1H), 6.27 (dd,J=16.8, 1.8 Hz, 1H), 5.81 (dd, J=10.0, 1.8 Hz, 1H); ESIMS m/z: [M+H]⁺325.

Example 44

Step 1

5-(4-Ethoxyphenoxy)pyridin-3-amine (Compound 44-1)

Compound 44-1 (15.0 mg, 17%) was obtained in the same manner as step 1of example 41, using 1-ethoxy-4-iodobenzene.

¹H NMR (400 MHz, CDCl₃, δ): 7.79 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz,1H), 7.00-6.95 (m, 2H), 6.91-6.86 (m, 2H), 6.50 (t, J=2.3 Hz, 1H), 4.02(q, J=7.0 Hz, 2H), 3.67 (br, 2H), 1.42 (t, J=7.0 Hz, 3H);

ESIMS m/z: [M+H]⁺ 231.

Step 2

N-{5-(4-Ethoxyphenoxy)pyridin-3-yl}acrylamide (Compound 102)

Compound 102 (9.90 mg, 54%) was obtained in the same manner as step 2 ofexample 38, using compound 44-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.41 (br, 1H), 8.52 (d, J=2.3 Hz, 1H),8.06 (d, J=2.3 Hz, 1H), 7.68 (t, J=2.3 Hz, 1H), 7.10-7.05 (m, 2H),7.02-6.96 (m, 2H), 6.38 (dd, J=17.0, 10.0 Hz, 1H), 6.25 (dd, J=17.0, 1.8Hz, 1H), 5.79 (dd, J=10.0, 1.8 Hz, 1H), 4.03 (q, J=7.0 Hz, 2H), 1.34 (t,J=7.0 Hz, 3H)

ESIMS m/z: [M+H]⁺ 285.

Example 45

Step 1

5-((5-(Trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-amine (Compound 45-1)

Compound 45-1 (31.0 mg, 34%) was obtained in the same manner as step 1of example 41, using 3-iodo-5-(trifluoromethyl)pyridine.

¹H NMR (400 MHz, CDCl₃, δ): 8.66 (br, 1H), 8.59 (d, J=2.3 Hz, 1H), 7.98(d, J=2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.50 (br, 1H), 6.66 (t, J=2.3Hz, 1H), 3.86 (br, 2H); ESIMS m/z: [M+H]⁺ 256.

Step 2

N-(5-[{5-(Trifluoromethyl)pyridin-3-yl}oxy]pyridin-3-yl)acrylamide(Compound 107)

Compound 107 (13.0 mg, 34%) was obtained in the same manner as step 2 ofexample 38, using compound 45-1.

¹H NMR (DMSO-d₆, δ): 10.56 (br, 1H), 8.84 (br, 1H), 8.79 (d, J=2.3 Hz,1H), 8.65 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.7 Hz, 1H), 8.05 (br, 1H), 7.94(t, J=2.3 Hz, 1H), 6.42 (dd, J=17.2, 10.0 Hz, 1H), 6.28 (dd, J=17.2, 1.8Hz, 1H), 5.82 (dd, J=10.0, 1.8 Hz, 1H); ESIMS m/z: [M+H]⁺ 310.

Example 46

Step 1

5-((2-(Trifluoromethyl)pyridin-4-yl)oxy)pyridin-3-amine (Compound 46-1)

Compound 46-1 (53.0 mg, 43%) was obtained in the same manner as step 1of example 41, using 4-iodo-2-(trifluoromethyl)pyridine.

¹H NMR (400 MHz, CDCl₃, δ): 8.59 (d, J=5.9 Hz, 1H), 8.05 (d, J=2.3 Hz,1H), 7.87 (d, J=2.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.01 (dd, J=5.9, 2.3 Hz,1H), 6.72 (t, J=2.3 Hz, 1H), 3.91 (br, 2H);

ESIMS m/z: [M+H]⁺ 256.

Step 2

N-(5-[{2-(Trifluoromethy)pyridin-4-yl}oxy]pyridin-3-yl)acrylamide(Compound 108)

Compound 108 (40.0 mg, 63%) was obtained in the same manner as step 2 ofexample 38, using compound 46-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.64 (br, 1H), 8.72 (d, J=2.3 Hz, 1H),8.68 (d, J=5.4 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.11 (t, J=2.3 Hz, 1H),7.59 (d, J=2.3 Hz, 1H), 7.29 (dd, J=5.4, 2.3 Hz, 1H), 6.44 (dd, J=17.0,10.0 Hz, 1H), 6.30 (dd, J=17.0, 1.8 Hz, 1H), 5.84 (dd, J=10.0, 1.8 Hz,1H);

ESIMS m/z: [M+H]⁺ 310.

Example 47

Step 1

5-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]pyridin-3-amine (Compound 47-1)

Compound 47-1 (99.0 mg, 73%) was obtained in the same manner as step 1of example 41, using 2-iodo-5-(trifluoromethyl)pyridine.

¹H NMR (400 MHz, CDCl₃, δ): 8.44 (br, 1H), 8.00 (br, 1H), 7.95-7.89 (m,2H), 7.06 (d, J=8.6 Hz, 1H), 6.83 (t, J=2.3 Hz, 1H), 3.81 (br, 2H);

ESIMS m/z: [M+H]⁺ 256.

Step 2

N-(5-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]pyridin-3-yl)acrylamide(Compound 109)

Compound 109 (82.0 mg, 68%) was obtained in the same manner as step 2 ofexample 38, using compound 47-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.57 (br, 1H), 8.66 (d, J=2.3 Hz, 1H),8.59 (br, 1H), 8.33-8.23 (m, 2H), 8.10 (t, J=2.3 Hz, 1H), 7.38 (d, J=8.6Hz, 1H), 6.44 (dd, J=16.8, 10.0 Hz, 1H), 6.29 (dd, J=16.8, 1.8 Hz, 1H),5.83 (dd, J=10.0, 1.8 Hz, 1H);

ESIMS m/z: [M+H]⁺ 310.

Example 48

Step 1

5-((6-Isopropoxypyridin-3-yl)oxy)pyridin-3-amine (Compound 48-1)

Compound 48-1 (26.0 mg, 23%) was obtained in the same manner as step 1of example 41, using 5-iodo-2-(isopropoxy)pyridine.

¹H NMR (400 MHz, CDCl₃, δ): 7.95 (d, J=3.2 Hz, 1H), 7.82 (d, J=2.3 Hz,1H), 7.77 (d, J=2.3 Hz, 1H), 7.33-7.26 (m, 1H), 6.69 (d, J=8.6 Hz, 1H),6.52 (t, J=2.3 Hz, 1H), 5.29-5.20 (m, 1H), 3.71 (br, 2H), 1.36 (d, J=6.8Hz, 6H);

ESIMS m/z: [M+H]⁺ 246.

Step 2

N-[5-{(6-Isopropoxypyridin-3-yl)oxy}pyridin-3-yl]acrylamide (Compound110)

Compound 110 (17.0 mg, 54%) was obtained in the same manner as step 2 ofexample 38, using compound 48-1.

¹H-NMR (400 MHz, DMSO-d₆, δ): 10.45 (br, 1H), 8.56 (d, J=2.3 Hz, 1H),8.11 (d, J=2.3 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.71 (t, J=2.3 Hz, 1H),7.59 (dd, J=9.1, 2.7 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 6.39 (dd, J=16.8,10.0 Hz, 1H), 6.26 (dd, J=16.8, 1.8 Hz, 1H), 5.80 (dd, J=10.0, 1.8 Hz,1H), 5.26-5.15 (m, 1H), 1.31 (d, J=5.9 Hz, 6H);

ESIMS m/z: [M+H]⁺ 300.

The following compounds were synthesized in accordance with thesynthesis method of compound 95.

N-{5-(3-Methoxyphenoxy)pyridin-3-yl}acrylamide (Compound 97)

ESIMS m/z: [M+H]⁺ 271.

N-{5-(4-Methoxyphenoxy)pyridin-3-yl}acrylamide (Compound 98)

ESIMS m/z: [M+H]⁺ 271.

N-{5-(4-Cyanophenoxy)pyridin-3-yl}acrylamide (Compound 99)

ESIMS m/z: [M+H]⁺ 266.

N-{5-(3-Ethoxyphenoxy)pyridin-3-yl}acrylamide (Compound 101)

ESIMS m/z: [M+H]⁺ 285.

N-{5-(4-Isopropoxyphenoxy)pyridin-3-yl}acrylamide (Compound 103)

ESIMS m/z: [M+H]⁺ 299.

N-[5-{4-(Benzyloxy)phenoxy}pyridin-3-yl]acrylamide (Compound 104)

ESIMS m/z: [M+H]⁺ 347.

N-{5-(3,4-Dichlorophenoxy)pyridin-3-yl}acrylamide (Compound 105)

ESIMS m/z: [M+H]⁺ 309.

N-[5-{3-Fluoro-4-(trifluoromethyl)phenoxy}pyridin-3-yl]acrylamide(Compound 106)

ESIMS m/z: [M+H]⁺ 327.

Example 49

Step 1

8-Phenoxyquinolin-5-amine (Compound 49-1)

Compound 49-1 (17.9 mg, 10%) was obtained in the same manner as step 4of example 4, using 5-aminoguinolin-8-ol.

¹H NMR (300 MHz, CDCl₃, δ): 8.94 (dd, J=4.0, 1.5 Hz, 1H), 8.22 (dd,J=8.6, 1.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.06-7.00(m, 4H), 6.77 (d, J=8.4 Hz, 1H)

ESIMS m/z: [M+H]⁺ 237.

Step 2

N-(8-Phenoxyquinolin-5-yl)acrylamide (Compound 111)

Compound 111 (8.3 mg, 40%) was obtained in the same manner as step 5 ofexample 1, using compound 49-1.

¹H NMR (300 MHz, CDCl₃, δ): 9.02 (s, 1H), 8.23 (d, J=7.3 Hz, 1H),7.70-7.62 (m, 1H), 7.54-7.46 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.21-7.13(m, 3H), 7.05 (d, J=8.4 Hz, 1H), 6.57-6.43 (m, 2H), 5.87 (d, J=9.9 Hz,1H)

ESIMS m/z: [M+H]⁺ 291.

Example 50

Step 1

8-Chloro-2-methyl-5-nitroquinoline (Compound 50-1)

8-Chloro-2-methylquinoline (0.50 g, 2.28 mmol) was added to a liquidmixture of concentrated sulfuric acid (2.5 mL), concentrated nitric acid(5.0 mL), and fuming nitric acid (1.0 mL) under ice cooling. The mixturewas slowly stirred at 65° C. for 16 hours. The mixture was cooled toroom temperature, and water was added to the mixture. The organic layerwas extracted with tert-butyl methyl ether, washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=100/0→80/20) to obtain compound50-1 (0.35 g, 56%).

¹H NMR (400 MHz, DMSO-d6, δ): 8.77 (d, J=8.8 Hz, 1H), 8.34 (d, J=8.4 Hz,1H), 8.10 (d, J=8.8 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 2.76 (s, 3H).

Step 2

2-Methyl-5-nitro-8-phenoxyquinoline (Compound 50-2)

Compound 50-1 (0.35 g, 1.57 mmol) was dissolved in DMF (5.0 mL), andphenol (0.11 g, 1.89 mmol) and cesium carbonate (1.20 g, 3.94 mmol) wereadded to the solution. The mixture was stirred at 90° C. for 3 hours.The mixture was cooled to room temperature, and water was added to themixture. The organic layer was extracted with tert-butyl methyl ether,washed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=80/20→70/30) to obtaincompound 50-2 (0.29 g, 56%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.91 (d, J=9.2 Hz, 1H), 8.38 (d, J=8.8 Hz,1H), 7.78 (d, J=9.2 Hz, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.32 (t, J=7.2 Hz,1H), 7.25 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.8 Hz, 1H), 2.72 (s, 3H).

Step 3

2-Methyl-8-phenoxyquinolin-5-amine (Compound 50-3)

Compound 50-2 (0.28 g, 1.00 mmol) was suspended in ethanol (5.0 mL) andwater (2.5 mL), and iron (0.27 g, 5.00 mmol) and ammonium chloride (0.26g, 5.00 mmol) were added to the suspension. The mixture was refluxed for2 hours. The mixture was cooled to room temperature, and dichloromethane(30 mL) was added to the mixture. The mixture was filtered with Celite®.The organic layer was washed with water (10 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtaincompound 50-3 (0.16 g, 66%).

¹H NMR (400 MHz, DMSO-d6, δ): 8.43 (d, J=8.8 Hz, 1H), 7.29-7.20 (m, 3H),7.12 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 2H),6.62 (d, J=8.0 Hz, 1H), 5.81 (s, 2H), 2.50 (s, 3H).

Step 4

N-(2-Methyl-8-phenoxyquinolin-5-yl)acrylamide (Compound 112)

Compound 112 (51.0 mg, 28%) was obtained in the same manner as step 5 ofexample 1, using compound 50-3 (0.15 g, 0.60 mmol).

¹H NMR (400 MHz, DMSO-d6, δ): 10.16 (s, 1H), 8.36 (d, J=8.7 Hz, 1H),7.71 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.38-7.33 (m, 2H), 7.23(d, J=8.4 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 6.97 (d, J=7.8 Hz, 2H), 6.66(dd, J=16.8, 10.2 Hz, 1H), 6.31 (dd, J=17.1, 1.8 Hz, 1H), 5.82 (dd,J=10.2, 1.5 Hz, 1H), 2.60 (s, 3H)

ESIMS m/z: [M+H]⁺ 305.

The following compounds were synthesized in accordance with thesynthesis method of compound 112.

N-{8-(3-Chlorophenoxy)-2-methylquinolin-5-yl}acrylamide (Compound 115)

ESIMS m/z: [M+H]⁺ 339.

N-{8-(4-Chlorophenoxy)-2-methylquinolin-5-yl}acrylamide (Compound 117)

ESIMS m/z: [M+H]⁺ 339.

Example 51

Step 1

8-(2-Chlorophenoxy)-5-nitroquinoline (Compound 51-1)

Compound 51-1 (30.0 mg, 40%) was obtained in the same manner as step 2of example 50, using 8-fluoro-5-nitroquinoline.

¹H NMR (400 MHz, CDCl₃, δ): 9.24 (dd, J=9.2, 1.6 Hz, 1H), 9.14 (dd,J=4.0, 1.2 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.8, 4.0 Hz,1H), 7.58-7.55 (m, 1H), 7.40-7.38 (m, 1H), 7.32-7.26 (m, 2H), 6.74 (d,J=8.8 Hz, 1H).

Step 2

8-(2-Chlorophenoxy)quinolin-5-amine (Compound 51-2)

Compound 51-2 (20.0 mg, 60%) was obtained in the same manner as step 3of example 50, using compound 51-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.95 (dd, J=4.4, 1.6 Hz, 1H), 8.21 (dd,J=8.4, 1.2 Hz, 1H), 7.47-7.41 (m, 2H), 7.12-7.10 (m, 1H), 7.04-7.00 (m,2H), 6.84-6.82 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.11 (bs, 2H).

Step 3

N-{8-(2-Chlorophenoxy)quinolin-5-yl}acrylamide (Compound 113)

Compound 113 (150 mg, 70%) was obtained in the same manner as step 5 ofexample 1, using compound 51-2.

¹H-NMR (400 MHz, DMSO-d₆, δ): 10.22 (s, 1H), 8.90-8.89 (m, 1H),8.51-8.49 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.66-7.58 (m, 2H), 7.29-7.21(m, 2H), 7.15-7.11 (m, 1H), 6.77-6.75 (m, 1H), 6.67 (dd, J=16.8, 10.0Hz, 1H), 6.33 (dd, J=16.8, 1.6 Hz, 1H), 5.85-5.82 (m, 1H)

ESIMS m/z: [M+H]⁺ 325.

The following compounds were synthesized in accordance with thesynthesis method of compound 113.

N-{8-(3-Chlorophenoxy)quinolin-5-yl}acrylamide (Compound 114)

ESIMS m/z: [M+H]⁺ 325.

N-{8-(4-Chlorophenoxy)quinolin-5-yl}acrylamide (Compound 116)

ESIMS m/z: [M+H]⁺ 325.

N-{8-(3,4-Dichlorophenoxy)quinolin-5-yl}acrylamide (Compound 118)

ESIMS m/z: [M+H]⁺ 359.

N-[8-{(4,4-Difluorocyclohexyl)oxy}quinolin-5-yl]acrylamide (Compound120)

ESIMS m/z: [M+H]⁺ 333.

N-[8-{(Tetrahydro-2H-pyran-4-yl)oxy}quinolin-5-yl]acrylamide (Compound121)

ESIMS m/z: [M+H]⁺ 299.

N-[8-{(Tetrahydro-2H-pyran-3-yl)oxy}quinolin-5-yl]acrylamide (Compound122)

ESIMS m/z: [M+H]⁺ 299.

N-[8-{(4-Ethynylbenzyl)oxy}quinolin-5-yl]acrylamide (Compound 124)

ESIMS m/z: [M+H]⁺ 329.

cis-N-(8-[{4-(Trifluoromethyl)cyclohexyl}methoxy]quinolin-5-yl)acrylamide(Compound 127)

ESIMS m/z: [M+H]⁺ 379.

trans-N-(8-[{4-(Trifluoromethyl)cyclohexyl}methoxy]quinolin-5-yl)acrylamide(Compound 128)

ESIMS m/z: [M+H]⁺ 379.

N-[8-{(Tetrahydro-2H-pyran-4-methoxy}quinolin-5-yl]acrylamide (Compound129)

ESIMS m/z: [M+H]⁺ 313.

N-[8-{(Tetrahydro-2H-pyran-3-yl)methoxy}quinolin-5-yl]acrylamide(Compound 130)

ESIMS m/z: [M+H]⁺ 313.

N-[8-{(Tetrahydro-2H-pyran-2-yl)methoxy}quinolin-5-yl]acrylamide(Compound 131)

ESIMS m/z: [M+H]⁺ 313.

N-[8-{(2,2-Dimethyltetrahydro-2H-pyran-4-yl)methoxy}quinolin-5-yl]acrylamide(Compound 132)

ESIMS m/z: [M+H]⁺ 341.

Example 52

Step 1

8-(Cyclohexyloxy)-5-nitroquinoline (Compound 52-1)

5-Nitroquinolin-8-ol (0.25 g, 1.31 mmol) was dissolved in DMF (5.0 mL),and cyclohexyl bromide (0.42 g, 2.63 mmol) and cesium carbonate (1.20 g,3.94 mmol) were added to the liquid mixture. The liquid mixture wasstirred at 90° C. for 16 hours. The mixture was cooled to roomtemperature, and water was added to the mixture. The organic layer wasextracted with methyl tert-butyl ether, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=100/0→80/20) to obtain compound 52-1 (0.24 g, 67%).

¹H-NMR (300 MHz, DMSO-d₆, δ): 9.05-9.00 (m, 2H), 8.52 (d, J=9.0 Hz, 1H),7.85-7.81 (m, 1H), 7.42 (d, J=9.0 Hz, 1H), 4.84-4.78 (m, 1H), 2.06-1.37(m, 10H).

Step 2

8-(Cyclohexyloxy)quinolin-5-amine (Compound 52-2)

Compound 52-2 (0.17 g, 83%) was obtained in the same manner as step 3 ofexample 50, using compound 52-1.

¹H-NMR (300 MHz, DMSO-d₆, δ): 8.78 (dd, J=3.9, 1.5 Hz, 1H), 8.44 (dd,J=8.4, 1.2 Hz, 1H), 7.37 (dd, J=8.7, 4.2 Hz, 1H), 7.02 (d, J=8.4 Hz,1H), 6.62 (d, J=8.1 Hz, 1H), 5.47 (s, 2H), 4.35-4.29 (m, 1H), 1.98-1.90(m, 2H), 1.78-1.75 (m, 2H), 1.52-1.46 (m, 3H), 1.33-1.23 (m, 3H).

Step 3

N-{8-(Cyclohexyloxy)quinolin-5-yl}acrylamide (Compound 119)

Compound 119 (89 mg, 46%) was obtained in the same manner as step 5 ofexample 1, using compound 52-2.

¹H-NMR (300 MHz, DMSO-d₆, δ): 10.04 (s, 1H), 8.88 (dd, J=3.9, 1.5 Hz,1H), 8.30 (dd, J=8.7, 1.8 Hz, 1H), 7.63-7.55 (m, 2H), 7.24 (d, J=8.7 Hz,1H), 6.62 (dd, J=17.1, 10.2 Hz, 1H), 6.28 (dd, J=17.1, 1.8 Hz, 1H), 5.80(dd, J=10.2, 1.8 Hz, 1H), 4.62-4.56 (m, 1H), 2.05-2.01 (m, 2H),1.81-1.77 (m, 2H), 1.60-1.23 (m, 6H)

ESIMS m/z: [M+H]⁺ 297.

The following compounds were synthesized in accordance with thesynthesis method of compound 119.

N-{8-(Benzyloxy)quinolin-5-yl}acrylamide (Compound 123)

ESIMS m/z: [M+H]⁺ 305.

N-{8-(Cyclohexylmethoxy)quinolin-5-yl}acrylamide (Compound 125)

ESIMS m/z: [M+H]⁺ 311.

Example 53

Step 1

8-{(4,4-Difluorocyclohexyl)methoxy}-5-nitroquinoline (Compound 53-1)

Compound 53-1 (0.25 g, 38%) was obtained in the same manner as step 2 ofexample 50, using 8-fluoro-5-nitroquinoline.

¹H-NMR (400 MHz, DMSO-d₆, δ): 9.04-9.02 (m, 2H), 8.54 (d, J=9.2 Hz, 1H),7.85-7.82 (m, 1H), 7.36 (d, J=8.8 Hz, 1H), 4.22 (d, J=6.8 Hz, 2H),2.10-1.86 (m, 7H), 1.45-1.41 (m, 2H).

Step 2

8-{(4,4-Difluorocyclohexyl)methoxy}quinolin-5-amine (Compound 53-2)

Compound 53-2 (0.17 g, 78%) was obtained in the same manner as step 3 ofexample 50, using compound 53-1.

¹H-NMR (400 MHz, DMSO-d₆, δ): 8.79-8.78 (m, 1H), 8.45 (dd, J=8.4, 1.6Hz, 1H), 7.41-7.38 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz,1H), 5.40 (s, 2H), 3.92 (d, J=6.0 Hz, 2H), 2.07-1.78 (m, 7H), 1.40-1.31(m, 2H).

Step 3

N-[8-{(4,4-Difluorocyclohexyl)methoxy}quinolin-5-yl]acrylamide (Compound126)

Compound 126 (78 mg, 38%) was obtained in the same manner as step 5 ofexample 1, using compound 53-2.

¹H-NMR (400 MHz, DMSO-d₆, δ): 8.89 (dd, J=4.0, 1.2 Hz, 1H), 8.31 (d,J=7.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.60-7.57 (m, 1H), 7.20 (d, J=8.4Hz, 1H), 6.61 (dd, J=17.2, 10.4 Hz, 1H), 6.28 (dd, J=17.2, 2.0 Hz, 1H),5.79 (d, J=10.8 Hz, 1H), 4.06 (d, J=6.4 Hz, 2H), 2.07-1.81 (m, 7H),1.44-1.36 (m, 2H); ESIMS m/z: [M+H]⁺ 347.

Example 54

Step 1

8-Fluoroquinoline-5-carbonitrile (Compound 54-1)

5-Bromo-8-fluoroquinoline (0.50 g, 2.21 mmol) was dissolved DMF (11 mL),and tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) andzinc cyanide (0.39 g, 3.32 mmol) were added to the solution. The mixturewas subjected to a reaction at a temperature of 150° C. for 30 minutesusing a microwave reactor, Initiator, manufactured by Biotage. Themixture was cooled to room temperature, and a saturated aqueous sodiumbicarbonate solution was added to the mixture. The mixture was filteredwith Celite®. The organic layer was extracted with ethyl acetate, washedwith saturated saline, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (heptane/ethyl acetate=90/10→60/40) to obtaincompound 54-1 (0.36 g, 94%).

¹H NMR (400 MHz, CDCl₃, δ): 9.12 (dd, J=4.5, 1.5 Hz, 1H), 8.58 (dt,J=8.5, 1.5 Hz, 1H), 7.99 (dd, J=8.3, 4.5 Hz, 1H), 7.72 (dd, J=8.5, 4.0Hz, 1H), 7.50 (dd, J=9.6, 8.3 Hz, 1H)

ESIMS m/z: [M+H]⁺ 173.

Step 2

8-(3-Chlorophenoxy)quinoline-5-carbonitrile (Compound 54-2)

Compound 54-2 (73.9 mg, 91%) was obtained in the same manner as step 2of example 50, using compound 54-1 (50.0 mg, 0.29 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 9.12 (dd, J=4.0, 1.8 Hz, 1H), 8.59 (dd,J=8.5, 1.8 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.72 (dd, J=8.5, 4.0 Hz,1H), 7.40 (t, J=8.1 Hz, 1H), 7.28 (dd, J=1.9, 1.0 Hz, 1H), 7.22 (q,J=1.9 Hz, 1H), 7.11 (dq, J=8.1, 1.0 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H)

ESIMS m/z: [M+H]⁺ 281.

Step 3

{8-(3-Chlorophenoxy)quinolin-5-yl}methanamine (Compound 54-3)

Lithium aluminum hydride (35.2 mg, 0.93 mmol) was suspended in THF (4.0mL), and compound 54-2 (86.8 mg, 0.31 mmol) dissolved in THF (1.0 mL)was added to the suspension under ice cooling. The mixture was stirredat 60° C. for 2 hours. The mixture was cooled to 0° C., and water (0.04mL), a 4 mol/L aqueous sodium hydroxide solution (0.04 mL), and water(0.12 mL) were sequentially added to the mixture. The mixture wasstirred at room temperature for 30 minutes. The mixture was filteredwith Celite®. The organic layer was extracted with ethyl acetate, washedwith saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified byaminosilica gel column chromatography (chloroform/methanol=100/0→95/5)to obtain compound 54-3 as a crude product, which was used as it is inthe next reaction.

Step 4

N-[{8-(3-chlorophenoxy)quinolin-5-yl}methyl]acrylamide (Compound 133)

Compound 133 (3.0 mg, 3% over two steps) was obtained in the same manneras step 3 of example 17, using compound 54-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.99 (dd, J=4.0, 1.3 Hz, 1H), 8.47 (dd,J=8.5, 1.8 Hz, 1H), 7.54 (dd, J=8.5, 4.5 Hz, 1H), 7.44 (d, J=8.1 Hz,1H), 7.30 (d, J=8.1 Hz, 1H), 7.13-7.10 (m, 2H), 7.06 (t, J=2.0 Hz, 1H),7.03-7.00 (m, 1H), 6.37 (dd, J=16.9, 1.3 Hz, 1H), 6.09 (dd, J=17.1, 10.3Hz, 1H), 5.81 (br, 1H), 5.70 (dd, J=10.3, 1.3 Hz, 1H), 4.96 (d, J=5.8Hz, 2H)

ESIMS m/z: [M+H]⁺ 339.

Example 55

Step 1

8-(4-Chlorophenoxy)quinoline-5-carbonitrile (Compound 55-1)

Compound 55-1 (0.64 g, 98%) was obtained in the same manner as step 2 ofexample 50, using compound 54-1 (0.40 g, 2.32 mmol) and 4-chlorophenol.

¹H NMR (400 MHz, CDCl₃, δ): 9.12 (dd, J=4.5, 1.8 Hz, 1H), 8.58 (dd,J=8.5, 1.8 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.5, 4.5 Hz,1H), 7.44 (dq, J=12.6, 2.8 Hz, 2H), 7.16 (dq, J=12.6, 2.8 Hz, 2H), 6.96(d, J=8.5 Hz, 1H)

ESIMS m/z: [M+H]⁺ 281.

Step 2

{8-(4-Chlorophenoxy)quinolin-5-yl}methanamine (Compound 55-2)

Compound 55-2 was obtained as a crude product in the same manner as step3 of example 54, using compound 55-1 (20.0 mg, 0.071 mmol), and used asit is in the next reaction.

Step 3

N-[{8-(4-Chlorophenoxy)quinolin-5-yl}methyl]acrylamide (Compound 134)

Compound 134 (2.2 mg, 9% over two steps) was obtained in the same manneras step 3 of example 17, using compound 55-2.

¹H NMR (400 MHz, CDCl₃, δ): 9.00 (dd, J=4.0, 1.3 Hz, 1H), 8.46 (dd,J=8.8, 1.6 Hz, 1H), 7.54 (dd, J=8.5, 4.0 Hz, 1H), 7.40 (d, J=8.1 Hz,1H), 7.34-7.33 (m, 2H), 7.06-7.02 (m, 3H), 6.36 (dd, J=16.9, 1.0 Hz,1H), 6.08 (dd, J=16.9, 10.3 Hz, 1H), 5.79 (br, 1H), 5.70 (dd, J=10.3,1.0 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H)

ESIMS m/z: [M+H]⁺ 339.

Example 56(E)-N-[{8-(4-Chlorophenoxy)quinolin-5-yl}methyl]-4,4,4-trifluoro-2-butenamide(Compound 135)

Compound 135 (60.0 mg, 60%) was obtained in the same manner as step 3 ofexample 17, using compound 55-2 (70.0 mg, 0.25 mmol) and commerciallyavailable (E)-4,4,4-trifluoro-2-butenoyl chloride (46.8 mg, 0.30 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 8.96 (dd, J=4.0, 1.8 Hz, 1H), 8.39 (dd,J=8.5, 1.8 Hz, 1H), 7.52 (dd, J=8.5, 4.0 Hz, 1H), 7.40 (d, J=8.1 Hz,1H), 7.33 (dd, J=7.0, 2.0 Hz, 2H), 7.04-7.00 (m, 3H), 6.88-6.79 (m, 1H),6.46 (dd, J=15.3, 1.8 Hz, 1H), 6.15 (br, 1H), 4.95 (d, J=5.4 Hz, 2H)

ESIMS m/z: [M+H]⁺ 407.

Example 57

Step 1

8-(4-Bromophenoxy)quinoline-5-carbonitrile (Compound 57-1)

Compound 57-1 (0.12 g, 94%) was obtained in the same manner as step 2 ofexample 50, using compound 54-1 (70.0 mg, 0.41 mmol) and 4-bromophenol(84.0 mg, 0.49 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 9.12 (dd, J=4.3, 1.6 Hz, 1H), 8.58 (dd,J=8.5, 1.3 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.3, 4.3 Hz,1H), 7.59-7.57 (m, 2H), 7.12-7.08 (m, 2H), 6.97 (d, J=8.1 Hz, 1H)

ESIMS m/z: [M+H]⁺ 324.

Step 2

{8-(4-Bromophenoxy)quinolin-5-yl}methanamine (Compound 57-2)

Compound 57-1 (125.0 mg, 0.38 mmol) was dissolved in a 2 mol/L ammoniasolution in methanol (12 mL), and the solution was subjected to areaction using Raney Nickel CatCart® (manufactured by ThalesNanoTechnologies, Inc., 30 mm) in the full H₂ mode of H-Cube® at 25° C. Thesolvent was concentrated under reduced pressure to obtain compound 57-2as a crude product.

Step 3

N-[{8-(4-Bromophenoxy)quinolin-5-yl}ethyl]acrylamide (Compound 57-3)

Compound 57-3 (0.10 g, 70% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 57-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.99 (dd, J=4.0, 1.8 Hz, 1H), 8.46 (dd,J=8.5, 1.8 Hz, 1H), 7.54 (dd, J=8.5, 4.0 Hz, 1H), 7.48-7.47 (m, 2H),7.41 (d, J=8.1 Hz, 1H), 7.04-6.95 (m, 3H), 6.36 (dd, J=17.0, 1.3 Hz,1H), 6.07 (dd, J=17.0, 10.3 Hz, 1H), 5.75 (br, 1H), 5.70 (dd, J=10.3,1.3 Hz, 1H), 4.95 (d, J=5.8 Hz, 2H)

ESIMS m/z: [M+H]⁺ 383.

Step 4

N-[{8-(4-Cyclopropylphenoxy)quinolin-5-yl}methyl]acrylamide (Compound136)

Compound 57-3 (50.0 mg, 0.13 mmol) was dissolved in 1,4-dioxane (1.0mL), and added to the solution were bis(triphenylphosphine)palladium(II)chloride dichloromethane adduct (10.7 mg, 0.013 mmol),cyclopropylboronic acid (33.6 mg, 0.391 mmol), cesium carbonate (0.26 g,0.783 mmol), and water (0.1 mL). The mixture was fluxed for 1.5 hours.The mixture was cooled to room temperature, and saturated saline wasadded to the mixture. The mixture was filtered with Presep ((R);diatomaceous earth, granular type M, 4.5 g/25 mL), and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=90/10→50/50) to obtain compound136 (12.8 mg, 28%).

¹H NMR (400 MHz, CDCl₃, δ): 9.02 (dd, J=4.1, 1.4 Hz, 1H), 8.44 (dd,J=8.6, 1.4 Hz, 1H), 7.53 (dd, J=8.6, 4.1 Hz, 1H), 7.35 (d, J=7.7 Hz,1H), 7.11-7.04 (m, 4H), 6.90 (d, J=8.2 Hz, 1H), 6.35 (dd, J=17.2, 1.4Hz, 1H), 6.06 (dd, J=17.2, 10.2 Hz, 1H), 5.73 (br, 1H), 5.69 (dd,J=10.2, 1.4 Hz, 1H), 4.92 (d, J=5.9 Hz, 2H), 1.92 (tt, J=8.4, 3.9 Hz,1H), 0.98-0.96 (m, 2H), 0.70-0.69 (m, 2H)

ESIMS m/z: [M+H]⁺ 345.

Example 58

Step 1

8-{3-(Trifluoromethyl)phenoxy}quinoline-5-carbonitrile (Compound 58-1)

Compound 58-1 (86.4 mg, 95%) was obtained in the same manner as step 2of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and3-(trifluoromethyl)phenol (56.0 mg, 0.35 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 9.12 (dd, J=4.0, 1.5 Hz, 1H), 8.60 (dd,J=8.5, 1.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.5, 4.0 Hz,1H), 7.61-7.53 (m, 2H), 7.47 (s, 1H), 7.39 (dt, J=8.2, 1.7 Hz, 1H), 7.02(d, J=8.1 Hz, 1H)

ESIMS m/z: [M+H]⁺ 315.

Step 2

[8-{3-(Trifluoromethyl)phenoxy}quinolin-5-yl]methanamine (Compound 58-2)

Compound 58-2 was obtained as a crude product in the same manner as step2 of example 57, using compound 58-1 (86.4 mg, 0.28 mmol).

ESIMS m/z: [M+H]⁺ 319.

Step 3

N-([8-{3-(Trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 137)

Compound 137 (65.3 mg, 64% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 58-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.98 (dd, J=4.4, 1.6 Hz, 1H), 8.48 (dd,J=8.8, 1.6 Hz, 1H), 7.55 (dd, J=8.8, 4.4 Hz, 1H), 7.46-7.44 (m, 2H),7.40 (d, J=8.1 Hz, 1H), 7.34 (br, 1H), 7.26-7.26 (m, 1H), 7.12 (d, J=7.6Hz, 1H), 6.38 (dd, J=16.9, 1.3 Hz, 1H), 6.09 (dd, J=16.9, 10.3 Hz, 1H),5.82 (br, 1H), 5.71 (dd, J=10.3, 1.3 Hz, 1H), 4.97 (d, J=5.8 Hz, 2H)

ESIMS m/z: [M+H]⁺ 373.

The following compounds were synthesized in accordance with thesynthesis method of compound 137.

N-[{8-(3,4-Dichlorophenoxy)quinolin-5-yl}methyl]acrylamide (Compound140)

ESIMS m/z: [M+H]⁺ 373.

N-[{8-(3,5-Dichlorophenoxy)quinolin-5-yl}methyl]acrylamide (Compound141)

ESIMS m/z: [M+H]⁺ 373.

Example 59

Step 1

8-{4-(Trifluoromethyl)phenoxy}quinoline-5-carbonitrile (Compound 59-1)

Compound 59-1 (91.1 mg, 100%) was obtained in the same manner as step 2of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and4-(trifluoromethyl)phenol (56.0 mg, 0.35 mmol).

ESIMS m/z: [M+H]⁺ 315.

Step 2

[8-{4-(Trifluoromethy)phenoxy}quinolin-5-yl]methanamine (Compound 59-2)

Compound 59-2 was obtained as a crude product in the same manner as step2 of example 57, using compound 59-1 (91.1 mg, 0.29 mmol).

ESIMS m/z: [M+H]⁺ 319.

Step 3

N-([8-{4-(Trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 138)

Compound 138 (22.8 mg, 21% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 59-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.97 (dd, J=4.0, 1.5 Hz, 1H), 8.49 (dd,J=8.5, 1.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.54 (dd, J=8.8, 4.3 Hz,1H), 7.47 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.12 (d, J=8.5 Hz,2H), 6.38 (dd, J=17.1, 1.3 Hz, 1H), 6.09 (dd, J=17.1, 10.3 Hz, 1H), 5.79(br, 1H), 5.71 (dd, J=10.3, 1.3 Hz, 1H), 4.98 (d, J=5.4 Hz, 2H)

ESIMS m/z: [M+H]⁺ 373.

Example 60

Step 1

5-Cyano-8-{4-(trifluoromethyl)phenoxy}quinoline 1-oxide (Compound 60-1)

Compound 59-1 (0.15 g, 0.48 mmol) was dissolved in dichloromethane (5.0mL), and m-chloroperoxybenzoic acid (0.13 g, 0.57 mmol) was added to thesolution. After the mixture was stirred at room temperature overnight,m-chloroperoxybenzoic acid (0.13 g, 0.57 mmol) was further added to themixture. The mixture was stirred at room temperature overnight. Themixture was basified by the addition of a 4 mol/L aqueous sodiumhydroxide solution, and a saturated aqueous sodium thiosulfate solutionto the mixture for quenching. The organic layer was extracted withchloroform, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to obtain compound 60-1 as a crude product.

Step 2

2-Chloro-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile(Compound 60-2)

Compound 60-1 was dissolved in toluene (4.8 mL), and phosphoryl chloride(0.22 mL, 2.39 mmol) and diisopropylethylamine (0.42 mL, 2.39 mmol) wereadded to the solution. The mixture was subjected to a reaction at 80° C.for one hour. The mixture was cooled to room temperature, diluted withacetonitrile, and added dropwise to ice-cooled water. A saturatedaqueous sodium bicarbonate solution was added to the mixture. Theorganic layer was extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (heptane/ethylacetate=90/10→80/20) to obtain compound 60-2 (31.8 mg, 19% over twosteps).

¹H NMR (400 MHz, CDCl₃, δ): 8.52 (d, J=9.0 Hz, 1H), 7.87 (d, J=8.1 Hz,1H), 7.72 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 1H), 7.30-7.28 (m, 2H),7.06 (d, J=8.5 Hz, 1H)

ESIMS m/z: [M+H]⁺ 349.

Step 3

[2-Chloro-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methanamine(Compound 60-3)

Compound 60-3 was obtained as a crude product in the same manner as step2 of example 57, using compound 60-2 (31.8 mg, 0.091 mmol).

ESIMS m/z: [M+H]⁺ 353.

Step 4

N-([2-Chloro-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 139)

Compound 139 (27.5 mg, 29% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 60-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.45 (d, J=9.1 Hz, 1H), 7.61 (d, J=8.6 Hz,2H), 7.51 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.14 (dd, J=9.7,7.9 Hz, 3H), 6.37 (dd, J=17.0, 1.1 Hz, 1H), 6.08 (dd, J=17.0, 10.4 Hz,1H), 5.80 (br, 1H), 5.72 (dd, J=10.4, 1.1 Hz, 1H), 4.94 (d, J=5.9 Hz,2H)

ESIMS m/z: [M+H]⁺ 407.

Example 61

Step 1

8-{(6-Chloropyridin-3-yl)oxy}quinoline-5-carbonitrile (Compound 61-1)

Compound 61-1 (71.9 mg, 88%) was obtained in the same manner as step 2of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and6-chloropyridin-3-ol (45.0 mg, 0.35 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 9.10 (dd, J=4.0, 1.8 Hz, 1H), 8.60 (dd,J=8.5, 1.8 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.74(dd, J=8.5, 4.0 Hz, 1H), 7.49 (dd, J=8.8, 2.9 Hz, 1H), 7.41 (d, J=8.5Hz, 1H), 7.07 (d, J=8.1 Hz, 1H)

ESIMS m/z: [M+H]⁺ 282.

Step 2

[8-{(6-Chloropyridin-3-yl)oxy}quinolin-5-yl]methanamine (Compound 61-2)

Compound 61-2 was obtained as a crude product in the same manner as step2 of example 57, using compound 61-1 (71.0 mg, 0.25 mmol).

ESIMS m/z: [M+H]⁺ 286.

Step 3

N-([8-{(6-Chloropyridin-3-yl)oxy}quinolin-5-yl]methyl)acrylamide(Compound 142)

Compound 142 (27.7 mg, 32% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 61-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.97 (dd, J=4.3, 1.3 Hz, 1H), 8.49 (dd,J=8.5, 1.3 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.56 (dd, J=8.5, 4.0 Hz,1H), 7.46 (d, J=7.6 Hz, 1H), 7.36 (dd, J=8.8, 2.9 Hz, 1H), 7.30-7.29 (m,1H), 7.15 (d, J=7.6 Hz, 1H), 6.38 (dd, J=16.8, 1.3 Hz, 1H), 6.09 (dd,J=16.8, 10.3 Hz, 1H), 5.81 (s, 1H), 5.71 (dd, J=10.3, 1.3 Hz, 1H), 4.97(d, J=5.8 Hz, 2H); ESIMS m/z: [M+H]⁺ 340.

Example 62

Step 1

8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinoline-5-carbonitrile(Compound 62-1)

Compound 62-1 (71.0 mg, 78%) was obtained in the same manner as step 2of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and6-(trifluoromethyl)pyridin-3-ol (57.0 mg, 0.35 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 9.06 (dd, J=4.0, 0.9 Hz, 1H), 8.62 (dd,J=8.5, 0.9 Hz, 1H), 8.58 (d, J=2.7 Hz, 1H), 7.74-7.72 (m, 2H), 7.52 (dd,J=8.7, 2.9 Hz, 1H), 7.30-7.29 (m, 1H)

ESIMS m/z: [M+H]⁺ 316.

Step 2

(8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinolin-5-yl)methanamine(Compound 62-2)

Compound 62-2 was obtained as a crude product in the same manner as step2 of example 57, using compound 62-1 (71.0 mg, 0.23 mmol).

ESIMS m/z: [M+H]⁺ 320.

Step 3

N-{(8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinolin-5-yl)methyl}acrylamide(Compound 143)

Compound 143 (26.7 mg, 32% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 62-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.93 (dd, J=3.8, 1.6 Hz, 1H), 8.52-8.50 (m,2H), 7.61 (d, J=8.5 Hz, 1H), 7.56-7.52 (m, 2H), 7.34-7.29 (m, 2H), 6.38(d, J=17.1 Hz, 1H), 6.10 (dd, J=17.1, 10.1 Hz, 1H), 5.81 (br, 1H), 5.72(d, J=10.1 Hz, 1H), 5.00 (d, J=5.8 Hz, 2H)

ESIMS m/z: [M+H]⁺ 374.

Example 63

Step 1

2-(4-Chlorophenoxy)quinoline-4-carbonitrile (Compound 63-1)

2-Chloroquinoline-4-carbonitrile (0.10 g, 0.53 mmol) was dissolved inDMF (2 mL), and 4-chlorophenol (0.082 g, 0.64 mmol) was added to thesolution. The mixture was stirred using a microwave reactor at 150° C.for 30 minutes. Water was added to the mixture. Precipitated crystalswere filtered off, washed with water, and dried under reduced pressureto obtain compound 63-1 (145 mg, 97%).

¹H NMR (400 MHz, CDCl₃, δ): 8.13 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz,1H), 7.75 (t, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.50-7.40 (m, 2H),7.24-7.18 (m, 3H).

Step 2

2-{4-(Chlorophenoxy)quinolin-4-yl}methanamine (Compound 63-2)

Compound 63-2 (148 mg, quantitatively) was obtained in the same manneras step 3 of example 15, using compound 63-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.91 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz,1H), 7.62 (t, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.38 (t, J=8.8 Hz,2H), 7.21-7.20 (m, 3H), 4.36 (s, 2H).

Step 3

N-[{2-(4-Chlorophenoxy)quinolin-4-yl}methyl]acrylamide (Compound 144)

Compound 144 (118 mg, 68%) was obtained in the same manner as step 5 ofexample 1, using compound 63-2.

¹H-NMR (400 MHz, DMSO-d₆, δ): 8.81 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.67(s, 2H), 7.52 (d, J=8.8 Hz, 3H), 7.30 (d, J=8.8 Hz, 2H), 7.09 (s, 1H),6.36 (dd, J=17.1, 10.2 Hz, 1H), 6.19 (d, J=17.1 Hz, 1H), 5.69 (d, J=10.2Hz, 1H), 4.87 (d, J=5.4 Hz, 2H)

ESIMS m/z: [M+H]⁺ 339.

The following compounds were synthesized in accordance with thesynthesis method of compound 144.

(E)-N-[{2-(4-Chlorophenoxy)quinolin-4-yl}methyl]-4,4,4-trifluoro-2-butenamide(Compound 145)

ESIMS m/z: [M+H]⁺ 407.

N-([2-{(6-Chloropyridin-3-yl)oxy}quinolin-4-yl]methyl)acrylamide(Compound 148)

ESIMS m/z: [M+H]⁺ 340.

Example 64

Step 1

2-{4-(Trifluoromethyl)phenoxy}quinoline-4-carbonitrile (Compound 64-1)

Compound 64-1 (129 mg, 52%) was obtained in the same manner as step 1 ofexample 63, using 2-chloroquinoline-4-carbonitrile.

¹H NMR (400 MHz, CDCl₃, δ): 8.16-8.12 (m, 1H), 7.86-7.71 (m, 4H),7.66-7.62 (m, 1H), 7.52 (s, 1H), 7.39 (d, J=8.8 Hz, 2H).

Step 2

[2-{4-(Trifluoromethyl)phenoxy}quinolin-4-yl]methanamine (Compound 64-2)

Compound 64-2 (127 mg, quantitatively) was obtained in the same manneras step 3 of example 15, using compound 64-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.92 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.5 Hz,1H), 7.68-7.61 (m, 3H), 7.47 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H),7.29-7.26 (m, 2H), 4.43-4.40 (m, 2H).

Step 3

N-([2-{4-(Trifluoromethyl)phenoxy}quinolin-4-yl]methyl)acrylamide(Compound 146)

Compound 146 (29 mg, 41%) was obtained in the same manner as step 5 ofexample 1, using compound 64-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.94 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.3 Hz,1H), 7.68-7.64 (m, 3H), 7.49 (t, J=8.3 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H),7.08 (s, 1H), 6.40 (d, J=17.1 Hz, 1H), 6.18 (dd, J=17.1, 10.2 Hz, 1H),5.98 (s, 1H), 5.75 (d, J=10.2 Hz, 1H), 5.01 (d, J=6.3 Hz, 2H)

ESIMS m/z: [M+H]⁺ 373.

Example 65(E)-4,4,4-Trifluoro-N-([2-{4-(trifluoromethyl)phenoxy}quinolin-4-yl]methyl)-2-butenamide(Compound 147)

Compound 147 (19 mg, 23%) was obtained in the same manner as in example18, using compound 64-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.90 (d, J=8.1 Hz, 1H), 7.81 (d, J=8.1 Hz,1H), 7.71-7.64 (m, 3H), 7.50 (t, J=8.1 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H),7.08 (s, 1H), 6.90-6.85 (m, 1H), 6.54 (dd, J=15.1, 2.0 Hz, 1H), 6.16(br, 1H), 5.03 (d, J=5.9 Hz, 2H)

ESIMS m/z: [M+H]⁺ 441.

Example 66

Step 1

2-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinoline-4-carbonitrile(Compound 66-1)

Compound 66-1 (76 mg, 91%) was obtained in the same manner as step 1 ofexample 63, using 2-chloroquinoline-4-carbonitrile.

¹H NMR (400 MHz, CDCl₃, δ): 8.76 (d, J=2.4 Hz, 1H), 8.17 (d, J=8.8 Hz,1H), 7.85-7.80 (m, 4H), 7.69-7.65 (m, 1H), 7.58 (s, 1H).

Step 2

(2-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinolin-4-yl)methanamine(Compound 66-2)

Compound 66-2 (70 mg, 91%) was obtained in the same manner as step 3 ofexample 15, using compound 66-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.75 (d, J=2.3 Hz, 1H), 7.94 (dd, J=8.4, 1.2Hz, 1H), 7.86 (dd, J=8.4, 2.3 Hz, 1H), 7.81-7.75 (m, 2H), 7.68-7.63 (m,1H), 7.50 (td, J=7.7, 1.2 Hz, 1H), 7.34 (s, 1H).

Step 3

N-{(2-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinolin-4-yl)methyl}acrylamide(Compound 149)

Compound 149 (72 mg, 90%) was obtained in the same manner as step 5 ofexample 1, using compound 66-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.73 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.3 Hz,1H), 7.86 (dd, J=8.3, 2.4 Hz, 1H), 7.78-7.77 (m, 2H), 7.67 (t, J=7.8 Hz,1H), 7.54-7.51 (m, 1H), 7.14 (s, 1H), 6.42 (dd, J=17.1, 1.5 Hz, 1H),6.21 (dd, J=17.1, 10.2 Hz, 1H), 5.99 (br, 1H), 5.78 (dd, J=10.2, 1.5 Hz,1H), 5.04 (d, J=5.9 Hz, 2H)

ESIMS m/z: [M+H]⁺ 374.

Example 67

Step 1

2-{(2-Chloropyridin-4-yl)oxy}quinoline-4-carbonitrile (Compound 67-1)

Compound 67-1 (75 mg, quantitatively) was obtained in the same manner asstep 1 of example 63, using 2-chloroquinoline-4-carbonitrile.

¹H NMR (400 MHz, CDCl₃, δ): 8.45 (d, J=5.8 Hz, 1H), 8.19 (d, J=7.8 Hz,1H), 7.92 (d, J=7.8 Hz, 1H), 7.83 (td, J=7.8, 1.3 Hz, 1H), 7.72-7.69 (m,1H), 7.54 (s, 1H), 7.37 (d, J=2.1 Hz, 1H), 7.23 (dd, J=5.8, 2.1 Hz, 1H).

Step 2

[2-{(2-Chloropyridin-4-yl)oxy}quinolin-4-yl]methanamine (Compound 67-2)

Compound 67-2 (72 mg, 94%) was obtained in the same manner as step 3 ofexample 15, using compound 67-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (d, J=5.4 Hz, 1H), 7.96 (d, J=8.5 Hz,1H), 7.89 (d, J=8.5 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.54 (t, J=7.6 Hz,1H), 7.31 (d, J=5.9 Hz, 2H), 7.19 (d, J=5.9 Hz, 1H), 4.42 (s, 2H).

Step 3

N-([2-{(2-Chloropyridin-4-yl)oxy}quinolin-4-yl]methyl)acrylamide(Compound 150)

Compound 150 (63 mg, 75%) was obtained in the same manner as step 5 ofexample 1, using compound 67-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.38 (d, J=5.8 Hz, 1H), 7.98 (d, J=8.8 Hz,1H), 7.88 (d, J=8.3 Hz, 1H), 7.74-7.69 (m, 1H), 7.58-7.54 (m, 1H), 7.32(d, J=2.1 Hz, 1H), 7.20 (dd, J=5.8, 2.1 Hz, 1H), 7.10 (s, 1H), 6.41 (dd,J=17.1, 1.3 Hz, 1H), 6.20 (dd, J=17.1, 10.2 Hz, 1H), 6.00 (br, 1H), 5.77(dd, J=10.2, 1.3 Hz, 1H), 5.04 (d, J=5.8 Hz, 2H)

ESIMS m/z: [M+H]⁺ 340.

Example 68

Step 1

2-[{2-(Trifluoromethyl)pyridin-4-yl}oxy]quinoline-4-carbonitrile(Compound 68-1)

Compound 68-1 (73 mg, 87%) was obtained in the same manner as step 1 ofexample 63, using 2-chloroquinoline-4-carbonitrile.

¹H NMR (400 MHz, CDCl₃, δ): 8.79 (d, J=5.5 Hz, 1H), 8.19 (d, J=8.5 Hz,1H), 7.90 (d, J=8.5 Hz, 1H), 7.86-7.81 (m, 1H), 7.72-7.70 (m, 2H), 7.57(s, 1H), 7.51 (dd, J=5.5, 2.2 Hz, 1H).

Step 2

(2-[{2-(Trifluoromethyl)pyridin-4-yl}oxy]quinolin-4-yl]methanamine(Compound 68-2)

Compound 68-2 (69 mg, 94%) was obtained in the same manner as step 3 ofexample 15, using compound 68-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.72 (d, J=5.5 Hz, 1H), 7.97 (d, J=7.8 Hz,1H), 7.87 (d, J=7.8 Hz, 1H), 7.71-7.69 (m, 2H), 7.54 (t, J=7.8 Hz, 1H),7.47 (dd, J=5.5, 2.2 Hz, 1H), 7.34 (s, 1H), 4.43 (s, 2H).

Step 3

N-{(2-[{2-(Trifluoromethyl)pyridin-4-yl}oxy]quinolin-4-yl)methyl}acrylamide(Compound 151)

Compound 151 (65 mg, 83%) was obtained in the same manner as step 5 ofexample 1, using compound 68-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.72 (d, J=5.4 Hz, H), 7.99 (dd, J=8.3, 1.0Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.68 (d, J=2.2 Hz,1H), 7.59-7.55 (m, 1H), 7.47 (dd, J=5.4, 2.2 Hz, 1H), 7.13 (s, 1H), 6.42(dd, J=16.9, 1.3 Hz, 1H), 6.20 (dd, J=16.9, 10.2 Hz, 1H), 5.99 (br, 1H),5.78 (dd, J=10.2, 1.3 Hz, 1H), 5.05 (d, J=5.9 Hz, 2H)

ESIMS m/z: [M+H]⁺ 374.

Example 69

Step 1

8-(4-Chlorophenoxy)chroman-4-ol (Compound 69-1)

Compound 69-1 (0.40 g, 80%) was obtained in the same manner as step 1 ofexample 15, using compound 25-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.34 (d, J=8.8 Hz, 2H), 7.22 (d, J=7.2 Hz,1H), 6.97-6.89 (m, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.47 (d, J=5.2 Hz, 1H),4.68-4.64 (m, 1H), 4.14-4.12 (m, 2H), 2.02-1.88 (m, 2H).

Step 2

8-(4-Chlorophenoxy)chromane-4-carbonitrile (Compound 69-2)

Compound 69-2 (0.02 g, 20%) was obtained in the same manner as step 2 ofexample 15, using compound 69-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.36 (d, J=8.8 Hz, 2H), 7.22 (d, J=7.6 Hz,1H), 7.06-6.97 (m, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.53 (t, J=6.0 Hz, 1H),4.18-4.14 (m, 2H), 2.33-2.24 (m, 2H).

Step 3

{8-(4-Chlorophenoxy)chroman-4-yl}methanamine (Compound 69-3)

Compound 69-3 (0.12 g, 79%) was obtained in the same manner as step 3 ofexample 15, using compound 69-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.33 (d, J=8.8 Hz, 2H), 7.10 (dd, J=6.4,2.8 Hz, 1H), 6.87-6.81 (m, 4H), 4.10-3.98 (m, 2H), 2.93-2.89 (m, 1H),2.75-2.64 (m, 2H), 2.03-1.89 (m, 2H).

Step 4

N-[{8-(4-Chlorophenoxy)chroman-4-yl}methyl]acrylamide (Compound 152)

Compound 152 (0.09 g, 69%) was obtained in the same manner as step 5 ofexample 1, using compound 69-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.37 (br, 1H), 7.34 (d, J=8.8 Hz, 2H),7.10-7.08 (m, 1H), 6.93-6.83 (m, 4H), 6.26 (dd, J=16.8, 10.0 Hz, 1H),6.11 (dd, J=17.2, 2.0 Hz, 1H), 5.62 (dd, J=10.0, 1.6 Hz, 1H), 4.14-4.02(m, 2H), 3.54-3.48 (m, 1H), 3.36-3.29 (m, 1H), 2.98-2.97 (m, 1H),1.93-1.78 (m, 2H);

ESIMS m/z: [M+H]⁺ 344.

Example 70N-(6-Bromo-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-3-yl)acrylamide(Compound 153)

Compound 51 (50 mg, 0.137 mmol) was dissolved in acetonitrile (1 mL),and N-bromosuccinimide (26.9 mg, 0.151 mmol) was added to the solution.The mixture was stirred at room temperature for 72 hours. Methanol wasadded to the reaction liquid, and the mixture was concentrated underreduced pressure. The residue was purified using a preparative HPLC[Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length100 mm; acetonitrile/0.05% aqueous TFA solution (30/70→40/60)] to obtaincompound 153 (26.9 mg, 47%).

¹H NMR (400 MHz, CDCl₃, δ): 8.33 (d, J=2.7 Hz, 1H), 7.56 (d, J=8.6 Hz,1H), 7.23 (dd, J=8.6, 2.7 Hz, 1H), 7.06 (dd, J=13.1, 2.3 Hz, 2H), 6.23(dd, J=17.0, 1.1 Hz, 1H), 5.98 (dd, J=17.0, 10.2 Hz, 1H), 5.80 (d, J=7.2Hz, 1H), 5.61 (dd, J=10.4, 1.4 Hz, 1H), 4.51-4.48 (m, 1H), 4.12-4.10 (m,1H), 4.04-4.01 (m, 1H), 3.10 (dd, J=17.2, 5.4 Hz, 1H), 2.85-2.80 (m,1H).

ESIMS m/z: [M+H]⁺ 443, 445.

Example 71

Step 1

8-[{2-(Trifluoromethyl)pyridin-5-yl}oxy]chroman-3-amine (Compound 71-1)

Compound 71-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available5-bromo-2-(trifluoromethyl)pyrimidine, and was used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 312.

Step 2

N-(8-[{2-(Trifluoromethyl)pyrimidin-5-yl}oxy]chroman-3-yl)acrylamide(Compound 155)

Compound 155 (130 mg, 44% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 71-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (s, 2H), 6.94-6.90 (m, 3H), 6.26-6.17(m, 2H), 6.00 (dd, J=17.0, 10.2 Hz, 1H), 5.56 (dd, J=10.4, 1.4 Hz, 1H),4.50-4.44 (m, 1H), 4.05-4.02 (m, 2H), 3.12 (dd, J=17.0, 5.2 Hz, 1H),2.82 (dd, J=17.2, 4.1 Hz, 1H).

ESIMS m/z: [M+H]⁺ 366.

Example 72

Step 1

8-[{6-(Trifluoromethyl)pyridazin-3-yl}oxy]chroman-3-amine (Compound72-1)

Compound 72-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available3-chloro-6-(trifluoromethyl)pyridazine, and was used as it is in thenext reaction.

ESIMS m/z: [M+H]⁺ 312.

Step 2

N-(8-[{6-(trifluoromethyl)pyridazin-3-yl}oxy]chroman-3-yl)acrylamide(Compound 156)

Compound 156 (158 mg, 53% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 72-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.74 (d, J=9.1 Hz, 1H), 7.29 (d, J=9.1 Hz,1H), 6.97-6.83 (m, 3H), 6.44 (d, J=8.2 Hz, 1H), 6.18 (dd, J=17.2, 1.4Hz, 1H), 6.05 (dd, J=17.0, 10.2 Hz, 1H), 5.53 (dd, J=10.0, 1.4 Hz, 1H),4.47-4.46 (m, 1H), 3.98-3.93 (m, 2H), 3.06 (dd, J=16.8, 5.4 Hz, 1H),2.74 (dd, J=16.8, 3.2 Hz, 1H).

ESIMS m/z: [M+H]⁺ 366.

Example 73

Step 1

8-[{5-(Trifluoromethyl)pyrazin-2-yl}oxy]chroman-3-amine (Compound 73-1)

Compound 73-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available2-chloro-5-(trifluoromethyl)pyrazine, and was used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 312.

Step 2

N-(8-[{5-(Trifluoromethyl)pyrazin-2-yl}oxy]chroman-3-yl)acrylamide(Compound 157)

Compound 157 (89 mg, 29% over two steps) was obtained in the same manneras step 5 of example 1, using compound 73-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.45 (s, 1H), 8.29 (s, 1H), 6.97-6.95 (m,2H), 6.89 (dd, J=9.1, 6.3 Hz, 1H), 6.18 (dd, J=17.7, 12.2 Hz, 2H), 5.98(dd, J=16.8, 10.4 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.48-4.48 (m, 1H),4.02-3.99 (m, 2H), 3.12 (dd, J=16.8, 5.4 Hz, 1H), 2.80 (d, J=16.8 Hz,1H).

ESIMS m/z: [M+H]⁺ 366.

Example 74

Step 1

8-[{4-(Trifluoromethyl)thio}phenoxy]chroman-3-amine (Compound 74-1)

Compound 74-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available(4-bromophenyl)(trifluoromethyl)sulfane, and was used as it is in thenext reaction.

ESIMS m/z: [M+H]⁺ 342.

Step 2

N-(8-[{4-(Trifluoromethyl)thio}phenoxy]chroman-3-yl)acrylamide (Compound158)

Compound 158 (48 mg, 15% over two steps) was obtained in the same manneras step 5 of example 1, using compound 74-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.50 (d, J=11.6 Hz, 2H), 6.87-6.84 (m, 5H),6.22 (d, J=16.8 Hz, 1H), 5.97 (dd, J=17.0, 10.2 Hz, 2H), 5.59 (d, J=10.9Hz, 1H), 4.52-4.49 (m, 1H), 4.14 (dt, J=11.2, 2.8 Hz, 1H), 4.03 (dd,J=11.3, 1.4 Hz, 1H), 3.13 (dd, J=17.0, 5.2 Hz, 1H), 2.83 (dt, J=17.2,2.5 Hz, 1H).

ESIMS m/z: [M+H]⁺ 396.

Example 75

Step 1

8-[{4-(Trifluoromethyl)sulfonyl}phenoxy]chroman-3-amine (Compound 75-1)

Compound 75-1 was obtained as a crude product in the same manner as step4 of example 4, using compound 28-2 and commercially available1-bromo-4-{(trifluoromethyl)sulfonyl}benzene, and was used as it is inthe next reaction.

ESIMS m/z: [M+H]⁺ 374.

Step 2

N-(8-[{4-(Trifluoromethyl)sulfonyl}phenoxy]chroman-3-yl)acrylamide(Compound 159)

Compound 159 (34 mg, 10% over two steps) was obtained in the same manneras step 5 of example 1, using compound 75-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.87 (d, J=9.3 Hz, 2H), 7.02 (dt, J=9.5, 2.5Hz, 2H), 6.98-6.88 (m, 3H), 6.23 (dd, J=16.8, 1.4 Hz, 1H), 5.97 (dd,J=17.0, 10.2 Hz, 1H), 5.86 (d, J=7.7 Hz, 1H), 5.61 (dd, J=10.4, 1.4 Hz,1H), 4.53-4.48 (m, 1H), 4.11 (dq, J=11.1, 2.0 Hz, 1H), 4.02 (dd, J=10.9,1.8 Hz, 1H), 3.14 (dd, J=17.2, 5.4 Hz, 1H), 2.85 (dt, J=16.9, 2.8 Hz,1H).

ESIMS m/z: [M+H]⁺ 428.

Example 76

Step 1

N-(8-Hydroxychroman-3-yl)acrylamide (Compound 76-1)

Compound 28-2 (0.20 g, 0.81 mmol) was dissolved in THF (4 mL) and water(4 mL), and sodium hydrogen carbonate (0.34 g, 4.06 mmol) and acryloylchloride (0.079 mL, 0.98 mmol) were added to the solution. The mixturewas stirred at room temperature for 1.5 hours. Water was added to themixture. The organic layer was extracted with ethyl acetate, washed witha 1 mol/L aqueous hydrochloric acid solution and saturated saline, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure to obtain compound 76-1 (0.17 g, 93%). ¹H NMR (400 MHz,DMSO-d₆, δ): 8.90 (s, 1H), 8.27 (d, J=6.8 Hz, 1H), 6.68-6.59 (m, 2H),6.51 (d, J=7.8 Hz, 1H), 6.35-6.23 (m, 1H), 6.12 (dd, J=17.1, 2.0 Hz,1H), 5.62-5.57 (m, 1H), 4.27-4.10 (m, 2H), 3.92 (dd, J=9.5, 6.6 Hz, 1H),3.01 (dd, J=16.5, 6.2 Hz, 1H), 2.69 (dd, J=16.5, 6.2 Hz, 1H);

ESIMS m/z: [M+H]⁺ 220.

Step 2

N-[8-{(4,4-Difluorocyclohexyl)methoxy}chroman-3-yl]acrylamide (Compound160)

Compound 76-1 (165 mg, 0.753 mmol), triphenylphosphine (237.0 mg, 0.903mmol), and (4,4-difluorocyclohexyl)methanol (136.0 mg, 0.347 mmol) weredissolved in THF (4 mL). Diisopropyl azodicarboxylate (0.19 mL) wasadded to the solution under cooling at 0° C. The mixture was stirred atroom temperature for 2 hours. Magnesium chloride hexahydrate (612 mg,3.01 mmol) and heptane (3.8 mL) were added to the mixture. The mixturewas stirred at 60° C. for 2 hours. Water was added to the mixture. Theorganic layer was extracted with ethyl acetate, washed with saturatedsaline, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/methanol=99/1→96/4) to obtain a crudeproduct. The crude product obtained was purified using a preparativeHPLC [Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm,length 100 mm; acetonitrile/0.05% aqueous TFA solution (30/70→40/60)] toobtain compound 160 (37.0 mg, 13%).

¹H NMR (400 MHz, CDCl₃, δ): 6.84 (t, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz,1H), 6.68 (d, J=7.6 Hz, 1H), 6.31 (dd, J=17.1, 1.3 Hz, 1H), 6.10-6.01(m, 2H), 5.64 (dd, J=10.3, 1.3 Hz, 1H), 4.63-4.56 (m, 1H), 4.35-4.28 (m,1H), 4.15 (dd, J=11.0, 2.0 Hz, 1H), 3.87-3.80 (m, 2H), 3.16 (dd, J=17.1,5.4 Hz, 1H), 2.87-2.78 (m, 1H), 2.21-2.08 (m, 2H), 2.07-1.92 (m, 3H),1.87-1.66 (m, 2H), 1.47-1.32 (m, 2H);

ESIMS m/z: [M+H]⁺ 352.

Example 77

Step 1

8-{(5-Chloropyrimidin-2-yl)oxy}chroman-3-amine hydrochloride (Compound77-1)

Compound 28-2 (0.20 g, 0.81 mmol) was dissolved in DMF (8 mL), andpotassium carbonate (0.56 g, 4.06 mmol) and 2,5-dichloropyrimidine (0.13g, 0.89 mmol) were added to the solution. The mixture was stirred at100° C. for 17 hours. Water was added to the mixture. The organic layerwas extracted with ethyl acetate, washed with saturated saline, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure to obtain compound 77-1 as a crude product, which was used asit is in the next reaction.

Step 2

N-[8-{(5-Chloropyrimidin-2-yl)oxy}chroman-3-yl]acrylamide (Compound 161)

Compound 161 (10.0 mg, 5% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 77-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.46 (s, 2H), 7.08 (dd, J=7.7, 1.6 Hz, 1H),7.04-6.94 (m, 2H), 6.29 (dd, J=17.2, 1.5 Hz, 1H), 6.08-5.95 (m, 2H),5.66 (dd, J=10.4, 1.5 Hz, 1H), 4.62-4.56 (m, 1H), 4.17-4.01 (m, 2H),3.20 (dd, J=17.0, 5.0 Hz, 1H), 2.87 (d, J=17.0 Hz, 1H);

ESIMS m/z: [M+H]⁺ 332.

Example 78

Step 1

2-Hydroxy-5-iodo-3-methoxybenzaldehyde (Compound 78-1)

Commercially available 2-hydroxy-3-methoxybenzaldehyde (2.00 g, 13.15mmol) was dissolved in chloroform (40 mL) and pyridine (20 mL), andsilver nitrate (2.10 g, 13.15 mmol) was added to the solution. Themixture was stirred at room temperature for 10 minutes. Iodinemonochloride (2.10 g, 12.15 mmol) was added to the mixture. The mixturewas stirred at room temperature for 3 hours. A saturated aqueous sodiumthiosulfate solution (50 mL) and a 2 mol/L aqueous hydrochloric acidsolution (50 mL) were added to the mixture. The organic layer wasextracted with dichloromethane, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain compound 78-1 (1.80 g,50%).

¹H NMR (300 MHz, DMSO-d₆, δ): 10.42 (s, 1H), 10.18 (s, 1H), 7.49 (d,J=1.8 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 3.86 (s, 3H).

Step 2

6-Iodo-8-methoxy-2H-chromene-3-carbonitrile (Compound 78-2)

Compound 78-2 (0.50 g, 22%) was obtained in the same manner as step 1 ofexample 23, using compound 78-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.52 (s, 1H), 7.31 (s, 1H), 7.25 (d, J=1.5Hz, 1H), 4.87 (s, 2H), 3.77 (s, 3H).

Step 3

8-Methoxy-6-(trifluoromethyl)-2H-chromene-3-carbonitrile (Compound 78-3)

Compound 78-2 (1.50 g, 4.80 mmol) was dissolved in DMF (15 mL), andadded to the solution were methyl 2,2-difluoro-2-(fluorosulfonyl)acetate(4.50 g, 24.03 mmol), hexamethylphosphoric triamide (4.20 g, 24.03mmol), and copper(I) iodide (0.76 g, 4.80 mmol). The mixture was stirredat 90° C. for 16 hours. Water was added to the mixture. The organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=80/20→70/30) to obtain compound 78-3 (0.65 g, 53%).

¹H NMR (300 MHz, DMSO-d₆, δ): 7.63 (s, 1H), 7.31 (d, J=4.2 Hz, 2H), 4.99(d, J=1.2 Hz, 2H), 3.85 (s, 3H).

Step 4

8-Methoxy-5-(trifluoromethyl)-2H-chromene-3-carboxylic acid (Compound78-4)

Compound 78-4 (0.60 g, 86%) was obtained in the same manner as step 2 ofexample 23, using compound 78-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 13.01 (bs, 1H), 7.50 (s, 1H), 7.38 (d,J=1.2 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 4.99 (d, J=1.6 Hz, 2H), 3.84 (s,3H).

Step 5

tert-Butyl {8-methoxy-6-(trifluoromethyl)-2H-chromen-3-yl)carbamate(Compound 78-5)

Compound 78-5 (0.60 g, 79%) was obtained in the same manner as step 3 ofexample 23, using compound 78-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 9.17 (s, 1H), 6.99 (d, J=0.8 Hz, 2H), 6.60(s, 1H), 4.75 (d, J=1.2 Hz, 2H), 3.80 (s, 3H), 1.45 (s, 9H).

Step 6

tert-Butyl {8-methoxy-6-(trifluoromethyl)chroman-3-yl)carbamate(Compound 78-6)

Compound 78-6 (0.55 g, 91%) was obtained in the same manner as step 4 ofexample 23, using compound 78-5.

¹H NMR (400 MHz, CDCl₃, δ): 6.95 (d, J=9.2 Hz, 2H), 4.85-4.83 (m, 1H),4.33-4.16 (m, 3H), 3.92 (s, 3H), 3.15-3.10 (m, 1H), 2.80-2.76 (m, 1H),1.43 (s, 9H).

Step 7

3-Amino-6-(trifluoromethyl)chroman-8-ol hydrobromide (Compound 78-7)

Compound 78-7 (0.35 g, 86%) was obtained in the same manner as step 6 ofexample 27, using compound 78-6.

ESIMS m/z: [M+H]⁺ 234.

Step 8

N-{8-Hydroxy-6-(trifluoromethyl)chroman-3-yl}acrylamide (Compound 78-8)

Compound 78-8 (0.07 g, 25%) was obtained in the same manner as step 1 ofexample 76, using compound 78-7.

¹H NMR (300 MHz, DMSO-d₆, δ): 9.65 (s, 1H), 8.28 (d, J=6.6 Hz, 1H), 6.90(d, J=12.9 Hz, 2H), 6.29 (dd, J=17.1, 9.9 Hz, 1H), 6.12 (dd, J=17.1, 2.4Hz, 1H), 5.60 (dd, J=9.9, 2.4 Hz, 1H), 4.25-4.18 (m, 2H), 4.04 (dd,J=11.1, 6.3 Hz, 1H), 3.11 (dd, J=16.5, 5.1 Hz, 1H), 2.75 (dd, J=16.8,6.0 Hz, 1H).

Step 9

N-{6-(Trifluoromethyl)-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-3-yl}acrylamide(Compound 162)

Compound 162 (0.03 g, 34%) was obtained in the same manner as step 1 ofexample 3, using compound 78-8.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.51 (d, J=2.8 Hz, 1H), 8.30 (d, J=6.8 Hz,1H), 7.82 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.46 (dd, J=8.4,2.4 Hz, 1H), 6.26 (dd, J=16.8, 10.0 Hz, 1H), 6.10 (dd, J=16.8, 2.0 Hz,1H), 5.60 (dd, J=10.4, 2.4 Hz, 1H), 4.29-4.27 (m, 1H), 4.16 (dd, J=10.8,2.0 Hz, 1H), 4.06 (dd, J=10.0, 6.4 Hz, 1H), 3.21 (dd, J=16.4, 4.8 Hz,1H), 2.87 (dd, J=17.6, 6.0 Hz, 1H);

ESIMS m/z: [M+H]⁺ 433.

Example 79

Step 1

8-Methoxy-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-one(Compound 79-1)

Compound 79-1 (0.11 g, 64%) was obtained in the same manner as step 1 ofexample 3, using compound 21-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.50 (d, J=2.5 Hz, 1H), 7.72 (d, J=8.6 Hz,1H), 7.66 (d, J=8.6 Hz, 1H), 7.34 (dd, J=8.6, 2.5 Hz, 1H), 6.73 (d,J=8.6 Hz, 1H), 4.68 (t, J=6.3 Hz, 2H), 3.84 (s, 3H), 2.87 (t, J=6.3 Hz,2H);

ESIMS m/z: [M+H]⁺ 340.

Step 2

8-Methoxy-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-amine(Compound 79-2)

Compound 79-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 79-1, and used as it is in the nextreaction.

Step 3

N-(8-Methoxy-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-yl)acrylamide(Compound 163)

Compound 163 (0.013 g, 14% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 79-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.44 (d, J=2.7 Hz, 1H), 7.58 (d, J=8.6 Hz,1H), 7.23 (dd, J=8.6, 2.7 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.66 (d,J=8.6 Hz, 1H), 6.37 (dd, J=17.1, 1.4 Hz, 1H), 6.13 (dd, J=17.1, 10.3 Hz,1H), 6.01 (d, J=7.7 Hz, 1H), 5.73 (dd, J=10.3, 1.4 Hz, 1H), 5.31-5.24(m, 1H), 4.45-4.37 (m, 1H), 4.32-4.22 (m, 1H), 3.77 (s, 3H), 2.34-2.22(m, 1H), 2.21-2.10 (m, 1H);

ESIMS m/z: [M+H]⁺ 395.

Example 80

Step 1

7-(3,4-Difluorophenoxy)-8-methoxychroman-4-one (Compound 80-1)

Compound 80-1 (0.12 g, 79%) was obtained in the same manner as step 1 ofexample 3, using compound 21-3.

¹H NMR (400 MHz, CDCl₃, δ): 7.64 (d, J=9.2 Hz, 1H), 7.15 (q, J=9.2 Hz,1H), 6.91-6.84 (m, 1H), 6.79-6.73 (m, 1H), 6.56 (d, J=9.2 Hz, 1H), 4.65(t, J=6.6 Hz, 2H), 3.89 (s, 3H), 2.84 (t, J=6.6 Hz, 2H);

ESIMS m/z: [M+H]⁺ 307.

Step 2

7-(3,4-Difluorophenoxy)-8-methoxychroman-4-amine (Compound 80-2)

Compound 80-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 80-1, and used as it is in the nextreaction.

Step 3

N-{7-(3,4-Difluorophenoxy)-8-methoxychroman-4-yl}acrylamide (Compound164)

Compound 164 (0.052 g, 39% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 80-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.08 (q, J=9.2 Hz, 1H), 6.94 (dd, J=8.5, 0.9Hz, 1H), 6.81-6.74 (m, 1H), 6.71-6.66 (m, 1H), 6.56 (d, J=9.2 Hz, 1H),6.37 (dd, J=17.1, 1.3 Hz, 1H), 6.11 (dd, J=17.1, 10.3 Hz, 1H), 5.82 (d,J=7.2 Hz, 1H), 5.72 (dd, J=10.3, L3 Hz, 1H), 5.27-5.20 (m, 1H),4.44-4.37 (m, 1H), 4.28-4.20 (m, 1H), 3.81 (s, 3H), 2.33-2.22 (m, 1H),2.18-2.09 (m, 1H);

ESIMS m/z: [M+H]⁺ 362.

Example 81

Step 1

7-{(4,4-Difluorocyclohexyl)methoxy}-8-methoxychroman-4-one (Compound81-1)

Compound 81-1 (0.16 g, 93%) was obtained in the same manner as step 2 ofexample 76, using compound 21-3.

¹H NMR (400 MHz, CDCl₃, δ): 7.67 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz,1H), 4.59 (t, J=6.3 Hz, 2H), 3.93 (d, J=6.3 Hz, 2H), 3.86 (s, 3H), 2.78(t, J=6.3 Hz, 2H), 2.18-2.13 (m, 2H), 2.03-1.95 (m, 3H), 1.88-1.71 (m,2H), 1.53-1.42 (m, 2H);

ESIMS m/z: [M+H]⁺ 327.

Step 2

7-{(4,4-Difluorocyclohexyl)methoxy}-8-ethoxychroman-4-amine (Compound81-2)

Compound 81-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 81-1, and used as it is in the nextreaction.

Step 3

N-[7-{(4,4-Difluorocyclohexyl)methoxy}-8-methoxychroman-4-yl]acrylamide(Compound 165)

Compound 165 (0.039 g, 24% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 81-2.

¹H NMR (400 MHz, CDCl₃, δ): 6.87 (d, J=8.5 Hz, 1H), 6.46 (d, J=8.5 Hz,1H), 6.34 (dd, J=17.1, 1.3 Hz, 1H), 6.11 (dd, J=17.1, 10.3 Hz, 1H), 6.03(d, J=7.2 Hz, 1H), 5.69 (dd, J=10.3, 1.3 Hz, 1H), 5.19-5.12 (m, 1H),4.39-4.29 (m, 1H), 4.23-4.13 (m, 1H), 3.85-3.80 (m, 5H), 2.26-2.04 (m,4H), 2.01-1.91 (m, 3H), 1.86-1.67 (m, 2H), 1.50-1.36 (m, 2H);

ESIMS m/z: [M+H]⁺ 382.

Example 82

Step 1

7-(Benzyloxy)-8-fluorochroman-4-one (Compound 82-1)

Compound 19-3 (0.50 g, 2.74 mmol) was dissolved in DMF (14 mL), andpotassium carbonate (0.76 g, 5.49 mmol) and benzyl bromide (0.39 mL,3.29 mmol) were added to the solution. The mixture was stirred at roomtemperature for 4 hours, Water was added to the mixture. Precipitatedcrystals were filtered off, washed with water, and dried under reducedpressure to obtain compound 82-1 (0.73 g, 98%).

¹H NMR (400 MHz, CDCl₃, δ): 7.64 (dd, J=8.9, 2.2 Hz, 1H), 7.46-7.32 (m,5H), 6.70 (dd, J=8.9, 7.0 Hz, 1H), 5.22 (s, 2H), 4.62 (t, J=6.4 Hz, 2H),2.81 (t, J=6.4 Hz, 2H);

ESIMS m/z: [M+H]⁺ 273.

Step 2

7-(Benzyloxy)-8-fluorochroman-4-amine (Compound 82-2)

Compound 82-2 (0.053 g, 53%) was obtained in the same manner as step 4of example 1, using compound 82-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.46-7.28 (m, 5H), 6.93 (dd, J=8.7, 2.0 Hz,1H), 6.56 (dd, J=8.7, 7.6 Hz, 1H), 5.12 (s, 2H), 4.37-4.26 (m, 2H), 4.00(t, J=5.2 Hz, 1H), 2.18-2.09 (m, 1H), 1.86-1.77 (m, 1H), 1.69-1.58 (m,2H).

Step 3

N-{7-(Benzyloxy)-8-fluorochroman-4-yl}acrylamide (Compound 166)

Compound 82-2 (0.014 g, 27%) was obtained in the same manner as step 3of example 17, using compound 82-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.46-7.30 (m, 5H), 7.12 (d, J=7.6 Hz, 1H),6.88-6.85 (m, 1H), 6.58 (t, J=8.1 Hz, 1H), 6.32 (d, J=17.1 Hz, 1H), 6.13(dd, J=17.1, 10.3 Hz, 1H), 5.69 (dd, J=10.3, 1.3 Hz, 1H), 5.19-5.11 (m,3H), 4.40-4.32 (m, 1H), 4.28-4.18 (m, 1H), 2.26-2.17 (m, 1H), 2.12-2.03(m, 1H);

ESIMS m/z: [M+H]⁺ 328.

The following compound was synthesized in accordance with the synthesismethod of compound 31.

N-{8-Fluoro-7-(4-fluorophenoxy)chroman-4-yl}acrylamide (Compound 167)

ESIMS m/z: [M+H]⁺ 332.

Example 83

Step 1

3-Chloro-1-(3-chloro-2,4-dihydrophenyl)propan-1-one (Compound 83-1)

Compound 83-1 (0.30 g, 38%) was obtained in the same manner as step 1 ofexample 1, using 2-chlorobenzene-1,3-diol.

¹H NMR (300 MHz, DMSO-d₆, δ): 13.09 (s, 1H), 11.52 (s, 1H), 7.82 (d,J=9.0 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 3.92 (t, J=6.3 Hz, 2H), 3.54 (t,J=6.0 Hz, 2H).

Step 2

8-Chloro-7-hydroxychroman-4-one (Compound 83-2)

Compound 83-2 (0.15 g, 60%) was obtained in the same manner as step 2 ofexample 1, using compound 83-1.

¹H NMR (300 MHz, DMSO-d₆, δ): 11.29 (s, 1H), 7.58 (d, J=9.0 Hz, 1H),6.69 (d, J=8.7 Hz, 1H), 4.59 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.6 Hz, 2H).

Step 3

8-Chloro-7-{(4-methoxybenzyl)oxy}chroman-4-one (Compound 83-3)

Compound 83-3 (0.35 g, 73%) was obtained in the same manner as step 1 ofexample 82, using compound 83-2.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.71 (d, J=8.7 Hz, 1H), 7.39 (d, J=8.7 Hz,2H), 7.03-6.95 (m, 3H), 5.22 (s, 2H), 4.62 (t, J=6.3 Hz, 2H), 3.75 (s,3H), 2.77 (t, J=6.3 Hz, 2H).

Step 4

8-Chloro-7-{(4-methoxybenzyl)oxy}chroman-4-amine (Compound 83-4)

Compound 83-4 (0.33 g, 94%) was obtained in the same manner as step 4 ofexample 1, using compound 83-3.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.36 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz,1H), 6.94 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 5.23-5.01 (m, 3H),4.35-4.18 (m, 2H), 3.74 (s, 3H), 2.08-1.92 (m, 1H), 1.85-1.69 (m, 1H).

Step 5

4-Amino-8-chlorochroman-7-ol hydrochloride (Compound 83-5)

Compound 83-4 (0.33 g, 1.03 mmol) was dissolved in dichloromethane (10mL), and a 4 mol/L hydrochloric acid solution in 1,4-dioxane (1.81 mL,7.24 mmol) was added to the solution. The mixture was stirred at roomtemperature for 18 hours. The mixture was concentrated under reducedpressure. The solid obtained was washed with dichloromethane to obtaincompound 83-5 (0.20 g, 82%).

¹H NMR (400 MHz, DMSO-d₆, δ): 10.41 (br, 1H), 8.58 (br, 3H), 7.28 (d,J=8.8 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.41-4.31 (m, 3H), 2.26-2.15 (m,2H).

Step 6

N-(8-Chloro-7-hydroxychroman-4-yl)acrylamide (Compound 83-6)

Compound 83-6 (0.10 g, 93%) was obtained in the same manner as step 1 ofexample 76, using compound 83-5.

ESIMS m/z: [M+H]⁺ 254.

Step 7

N-(8-Chloro-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-yl)acrylamide(Compound 168)

Compound 168 (0.13 g, 41%) was obtained in the same manner as step 1 ofexample 3, using compound 83-6.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.64 (d, J=8.0 Hz, 1H), 8.54 (d, J=2.4 Hz,1H), 7.90 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.4, 2.4 Hz, 1H), 7.24 (d,J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.29-6.19 (m, 2H), 5.66 (dd,J=9.6, 2.4 Hz, 1H), 5.17-5.14 (m, 1H), 4.44-4.32 (m, 2H), 2.16-2.12 (m,1H), 1.99-1.96 (m, 1H);

ESIMS m/z: [M+H]⁺ 328.

Example 84

Step 1

1-(3-Bromo-2,4-dihydrophenyl)-3-chloropropan-1-one (Compound 84-1)

Compound 84-1 (0.15 g, 21%) was obtained in the same manner as step 1 ofexample 1, using 2-bromobenzene-1,3-diol.

¹H NMR (300 MHz, DMSO-d₆, δ): 11.99 (br, 1H), 11.35 (br, 1H), 7.62 (d,J=8.7 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 4.59 (t, J=6.3 Hz, 2H), 2.72 (t,J=6.3 Hz, 2H).

Step 2

8-Bromo-7-hydroxychroman-4-one (Compound 84-2)

Compound 84-2 (0.080 g, 62%) was obtained in the same manner as step 2of example 1, using compound 84-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 11.34 (s, 1H), 7.62 (d, J=8.8 Hz, 1H),6.68 (d, J=8.8 Hz, 1H), 4.59 (t, J=6.4 Hz, 2H), 2.72 (t, J=6.4 Hz, 2H).

Step 3

8-Bromo-7-{(4-methoxybenzyl)oxy}chroman-4-one (Compound 84-3)

Compound 84-3 (0.55 g, 73%) was obtained in the same manner as step 1 ofexample 82, using compound 84-2.

¹H NMR (300 MHz, CDCl₃, δ): 7.85 (d, J=9.0 Hz, 1H), 7.37 (d, J=8.7 Hz,2H), 6.93-6.88 (m, 3H), 5.17 (s, 2H), 4.63 (t, J=6.6 Hz, 2H), 3.81 (s,3H), 2.79 (t, J=6.3 Hz, 2H).

Step 4

8-Bromo-7-{(4-methoxybenzyl)oxy}chroman-4-amine (Compound 84-4)

Compound 84-4 (0.50 g, 90%) was obtained in the same manner as step 4 ofexample 1, using compound 84-3.

ESIMS m/z: [M+H]⁺ 364.

Step 5

4-Amino-8-bromochroman-7-ol hydrochloride (Compound 84-5)

Compound 84-5 (0.25 g, 65%) was obtained in the same manner as step 5 ofexample 83, using compound 84-4.

ESIMS m/z: [M+H]⁺ 244.

Step 6

N-(8-Bromo-7-hydroxychroman-4-yl)acrylamide (Compound 84-6)

Compound 84-6 (0.15 g, 61%) was obtained in the same manner as step 1 ofexample 76, using compound 84-5.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.12 (s, 1H), 8.51 (d, J=8.0 Hz, 1H),6.93 (d, J=8.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 6.26-6.11 (m, 2H), 5.61(dd, J=9.6, 2.4 Hz, 1H), 5.01-4.96 (m, 1H), 4.34-4.29 (m, 1H), 4.22-4.00(m, 1H), 2.07-1.98 (m, 1H), 1.87-1.83 (m, 1H).

Step 7

N-(8-Bromo-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-yl)acrylamide(Compound 169)

Compound 169 (0.055 g, 23%) was obtained in the same manner as step 1 ofexample 3, using compound 84-6.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.64 (d, J=8.1 Hz, 1H), 8.53 (d, J=2.4 Hz,1H), 7.90 (d, J=8.7 Hz, 1H), 7.38 (dd, J=8.7, 2.4 Hz, 1H), 7.28 (d,J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.30-6.13 (m, 2H), 5.65 (dd,J=9.3, 2.7 Hz, 1H), 5.18-5.14 (m, 1H), 4.46-4.30 (m, 2H), 2.17-1.95 (m,2H);

ESIMS m/z: [M+H]⁺ 443.

Example 85

Step 1

4-Amino-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-8-olhydrobromide (Compound 85-1)

Compound 85-1 was obtained as a crude product in the same manner as step6 of example 27, using compound 79-2.

ESIMS m/z: [M−16]⁺ 310.

Step 2

N-(8-Hydroxy-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-yl)acrylamide(Compound 170)

Compound 170 (0.030 g, 16%) was obtained in the same manner as step 1 ofexample 76, using compound 85-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 9.20 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.44(d, J=2.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.26 (dd, J=8.4, 2.4 Hz, 1H),6.74-6.69 (m, 2H), 6.27 (dd, J=16.8, 7.2 Hz, 1H), 6.19-6.12 (m, 1H),5.64 (dd, J=9.6, 2.4 Hz, 1H), 5.11-5.09 (m, 1H), 4.34-4.32 (m, 1H),4.27-4.25 (m, 1H), 2.16-2.08 (m, 1H), 1.98-1.91 (m, 1H);

ESIMS m/z: [M+H]⁺ 381.

Example 86

Step 1

4-Amino-8-fluorochroman-7-ol (Compound 86-1)

Compound 82-1 (1.33 g, 4.87 mmol) was dissolved in ethanol (100 mL), andthe solution was subjected to a reaction using Pd/C CatCart®(manufactured by ThalesNano Technologies, Inc., 70 mm) in the full H₂mode of H-Cube® at 35° C. The solvent was concentrated under reducedpressure to obtain compound 86-1 as a crude product, which was used asit is in the next reaction.

Step 2

N-(8-Fluoro-7-hydroxychroman-4-yl)acrylamide (Compound 86-2)

Compound 86-2 (0.35 g, 29% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 86-1.

¹H NMR (400 MHz, CDCl₃, δ): 6.83 (d, J=10.1 Hz, 1H), 6.55 (t, J=8.4 Hz,1H), 6.34 (t, J=8.4 Hz, 1H), 6.13-6.07 (m, 2H), 5.70 (dd, J=10.1, 1.3Hz, 1H), 5.17-5.13 (m, 1H), 4.38-4.32 (m, 1H), 4.23-4.16 (m, 1H),2.28-2.18 (m, 1H), 2.15-2.07 (m, 1H);

ESIMS m/z: [M−H]⁺ 236.

Step 3

N-(8-Fluoro-7-[{2-(trifluoromethyl)pyrimidin-5-yl}oxy]chroman-4-yl)acrylamide(Compound 171)

Compound 171 (6.00 mg, 7%) was obtained in the same manner as step 3 ofexample 1, using compound 86-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.54 (s, 2H), 7.10 (dd, J=8.8, 1.4 Hz, 1H),6.75 (dd, J=8.8, 7.0 Hz, 1H), 6.40 (dd, J=17.0, 1.4 Hz, 1H), 6.13 (dd,J=17.0, 10.3 Hz, 1H), 5.80-5.75 (m, 2H), 5.34 (dd, J=13.5, 5.8 Hz, 1H),4.48-4.40 (m, 1H), 4.36-4.27 (m, 1H), 2.37-2.27 (m, 1H), 2.22-2.13 (m,1H);

ESIMS m/z: [M+H]⁺ 384.

Example 87N-(8-Ethoxy-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-yl)acrylamide(Compound 172)

Compound 170 (0.05 g, 0.131 mmol) was dissolved in DMF (2 mL), andpotassium carbonate (0.037 g, 0.263 mmol) and iodoethane (0.050 mL,0.657 mmol) were added to the solution. The mixture was stirred at 70°C. for one hour. The mixture was cooled to room temperature, and waterwas added to the mixture. The organic layer was extracted with ethylacetate, washed with water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=80/20→40/60) to obtaincompound 172 (0.030 g, 56%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.64 (d, J=8.0 Hz, 1H), 8.50 (d, J=2.7 Hz,1H), 7.87 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz,1H), 6.81 (d, J=8.4 Hz, 1H), 6.30-6.15 (m, 2H), 5.66-5.63 (m, 1H),5.12-5.10 (m, 1H), 4.34-4.22 (m, 2H), 3.93-3.86 (m, 2H), 2.13-2.09 (m,1H), 1.95-1.92 (m, 1H), 1.03 (t, J=7.2 Hz, 3H);

ESIMS m/z: [M+H]⁺ 409.

Example 88

Step 1

2-Aminobenzene-1,3-diol (Compound 88-1)

2-Nitrobenzene-1,3-diol (12.0 g, 77.41 mmol) was dissolved in ethanol(100 mL), and 10% palladium carbon (2.0 g) was added to the solution.The mixture was stirred under hydrogen atmosphere at room temperaturefor 18 hours. The mixture was filtered with Celite®, and the filtratewas concentrated under reduced pressure to obtain compound 88-1 (8.0 g,83%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.83 (br, 2H), 6.25 (br, 2H), 6.23-6.20(m, 3H).

Step 2

2-(Dimethylamino)benzene-1,3-diol (Compound 88-2)

Compound 88-1 (3.0 g, 24.0 mmol) was dissolved in THF (40 mL), and thesolution was cooled to 0° C. Formaldehyde (2.10 mL, 72.0 mmol) andsodium cyanoborohydride (2.20 g, 36.0 mmol) were added to the solution,and the mixture was stirred at room temperature for 18 hours. Water (50mL) was added to the mixture. The organic layer was extracted with ethylacetate, washed with water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=90/10→70/30) to obtaincompound 88-2 (1.80 g, 38%).

¹H NMR (300 MHz, DMSO-d₆, δ): 9.44 (br, 2H), 6.82 (t, J=8.1 Hz, 1H),6.29 (d, J=8.1 Hz, 2H), 2.77 (s, 6H).

Step 3

3-Chloro-1-{3-(dimethylamino)-2,4-dihydrophenyl}propan-1-one (Compound88-3)

Compound 88-3 (0.92 g, 33%) was obtained in the same manner as step 1 ofexample 1, using compound 88-2.

ESIMS m/z: [M+H]⁺ 244.

Step 4

8-(Dimethylamino)-7-hydroxychroman-4-one (Compound 88-4)

Compound 88-4 (0.35 g, 46%) was obtained in the same manner as step 2 ofexample 1, using compound 88-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 9.49 (br, 1H), 7.47 (d, J=8.4 Hz, 1H),6.52 (d, J=8.4 Hz, 1H), 4.52 (t, J=6.0 Hz, 2H), 2.68-2.67 (m, 8H).

Step 5

8-(Dimethylamino)-7-{(4-ethoxybenzyl)oxy}chroman-4-one (Compound 88-5)

Compound 88-5 (0.30 g, 54%) was obtained in the same manner as step 1 ofexample 82, using compound 88-4.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.51 (d, J=8.7 Hz, 1H), 7.39 (d, J=8.4 Hz,2H), 6.96 (d, J=8.4 Hz, 2H), 6.83 (d, J=9.0 Hz, 1H), 5.10 (s, 2H), 4.49(t, J=6.3 Hz, 2H), 3.75 (s, 3H), 2.70-2.67 (m, 8H).

Step 6

7-{(4-Methoxybenzyl)oxy}-N⁸,N⁸-dimethylchromane-4,8-diamine (Compound88-6)

Compound 88-6 (0.22 g, 73%) was obtained in the same manner as step 4 ofexample 1, using compound 88-5.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.36 (d, J=8.4 Hz, 2H), 6.95-6.92 (m, 3H),6.56 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.23-4.10 (m, 2H), 3.81-3.78 (m,1H), 3.74 (s, 3H), 2.64 (s, 6H), 1.95-1.89 (m, 1H), 1.68-1.63 (m, 1H).

Step 7

4-Amino-8-(dimethylamino)chroman-7-ol hydrochloride (Compound 88-7)

Compound 88-7 (0.10 g, 65%) was obtained in the same manner as step 5 ofexample 83, using compound 88-6.

ESIMS m/z: [M+H]⁺ 209.

Step 8

4-Acrylamide-8-(dimethylamino)chroman-7-yl acrylate (Compound 88-8)

Compound 88-8 (0.10 g, 65%) was obtained in the same manner as step 1 ofexample 76, using compound 88-7.

ESIMS m/z: [M+H]⁺ 317.

Step 9

N-{8-(Dimethylamino)-7-hydroxychroman-4-yl}acrylamide (Compound 88-9)

Compound 88-8 (0.12 g, 0.38 mmol) was dissolved in methanol (5 mL), andpotassium carbonate (0.10 g, 0.75 mmol) were added to the solution. Themixture was stirred at 80° C. for one hour. The mixture was left to coolto room temperature. Water (20 mL) was added to the mixture. The organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain compound 88-9(0.085 g, 85%).

¹H NMR (300 MHz, DMSO-d₅, δ): 8.52 (d, J=8.0 Hz, 1H), 8.35 (br, 1H),7.22 (d, J=8.8 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 6.25 (dd, J=17.2, 10.0Hz, 1H), 6.13 (dd, J=17.2, 2.8 Hz, 1H), 5.59 (dd, J=9.6, 2.4 Hz, 1H),4.95-4.91 (m, 1H), 4.28-4.11 (m, 2H), 2.65 (s, 6H), 2.08-1.96 (m, 1H),1.87-1.81 (m, 1H).

Step 10

N-{8-(Dimethylamino)-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-4-yl}acrylamide(Compound 173)

Compound 173 (0.019 g, 15%) was obtained in the same manner as step 1 ofexample 3, using compound 88-9.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.40 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz,1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.57 (d,J=8.4 Hz, 1H), 6.36 (dd, J=16.8, 1.2 Hz, 1H), 6.11 (dd, J=16.8, 10.0 Hz,1H), 5.82 (d, J=7.2 Hz, 1H), 5.72 (dd, J=10.0, 0.8 Hz, 1H), 5.26-5.21(m, 1H), 4.42-4.37 (m, 1H), 4.25-4.19 (m, 1H), 2.65 (s, 6H), 2.31-2.23(m, 1H), 2.17-2.09 (m, 1H);

ESIMS m/z: [M+H]⁺ 408.

Example 89

Step 1

4-(4-Chlorophenoxy)-3-methoxybenzonitrile (Compound 89-1)

Compound 89-1 (0.50 g, 58%) was obtained in the same manner as step 2 ofexample 50, using commercially available 4-fluoro-3-methoxybenzonitrile.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.67 (d, J=2.0 Hz, 1H), 7.46-7.41 (m, 3H),7.11 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 3.83 (s, 3H).

Step 2

4-(4-Chlorophenoxy)-3-hydroxybenzonitrile (Compound 89-2)

Compound 89-2 (0.40 g, 85%) was obtained in the same manner as step 1 ofexample 19, using compound 89-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.46 (s, 1H), 7.42 (d, J=9.2 Hz, 2H),7.32-7.31 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H).

Step 3

3-(Allyloxy)-4-(4-chlorophenoxy)benzonitrile (Compound 89-3)

Compound 89-2 (1.00 g, 4.08 mmol) was dissolved in DMF (10 mL), andpotassium carbonate (1.12 g, 8.16 mmol) and allyl chloride (0.40 mL,4.89 mmol) were added to the solution. The mixture was stirred at 80° C.for one hour. The mixture was cooled to room temperature, and water wasadded to the mixture. The organic layer was extracted with tert-butylmethyl ether, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=100/0→80/20) to obtain compound89-3 (1.00 g, 86%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.67 (d, J=1.8 Hz, 1H), 7.43-7.40 (m, 3H),7.16 (d, J=8.4 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 5.97-5.84 (m, 1H),5.25-5.17 (m, 2H), 4.65 (d, J=5.1 Hz, 2H).

Step 4

2-Allyl-4-(4-chlorophenoxy)-3-hydroxybenzonitrile (Compound 89-4)

Compound 89-3 (0.50 g, 1.75 mmol) was stirred using a microwave reactorat 180° C. for one hour. The mixture was cooled to room temperature, andethyl acetate was added to the mixture. The organic layer was washedwith water, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to obtain compound 89-4 (0.45 g, 90%).

¹H NMR (400 MHz, DMSO-d₆, δ): 9.99 (s, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.26(d, J=8.4 Hz, 1H), 7.08 (d, J=9.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 1H),5.99-5.89 (m, 1H), 5.07-4.98 (m, 2H), 3.55 (d, J=6.4 Hz, 2H).

Step 5

2-Allyl-6-(4-chlorophenoxy)-3-cyanophenyl acetate (Compound 89-5)

Compound 89-4 (0.50 g, 1.75 mmol) was dissolved in dichloromethane (10mL), and triethylamine (0.50 mL, 3.50 mmol) and acetic anhydride (0.35mL, 3.50 mmol) were added to the solution. The mixture was stirred atroom temperature for 2 hours. Dichloromethane was added to the mixture.The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=100/0−>90/10) to obtaincompound 89-5 (0.45 g, 78%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.74 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz,2H), 7.10 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 1H), 5.88-5.78 (m, 1H),5.11-5.04 (m, 2H), 3.52 (d, J=6.4 Hz, 2H), 2.30 (s, 3H).

Step 6

6-(4-Chlorophenoxy)-3-cyano-2-(oxiran-2-ylmethyl)phenyl acetate(Compound 89-6)

Compound 89-5 (0.40 g, 1.22 mmol) was dissolved in dichloromethane (10mL), and m-chloroperoxybenzoic acid (0.45 g, 1.83 mmol) was added to thesolution. The mixture was stirred at room temperature for 24 hours.Dichloromethane was added to the mixture. The organic layer was washedwith a 4 mol/L aqueous sodium hydroxide solution and a saturated aqueoussodium sulfate solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=100/0→80/20) to obtaincompound 89-6 (0.35 g, 74%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.75 (d, J=8.8 Hz, 1H), 7.51 (d, J=9.2 Hz,2H), 7.11 (d, J=9.2 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 3.12-3.04 (m, 3H),2.76-2.74 (m, 2H), 2.33 (s, 3H).

Step 7

1-Chloro-3-{3-(4-chlorophenoxy)-6-cyano-2-hydroxyphenyl}propan-2-ylacetate (Compound 89-7)

Compound 89-6 (6.00 g, 17.49 mmol) was dissolved in 1,4-dioxane (50 mL),and a 20% hydrochloric acid solution in 1,4-dioxane (15.96 mL, 87.46mmol) was added to the solution. The mixture was stirred at roomtemperature for 72 hours. Water was added to the mixture. The organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=90/10→80/20) to obtain compound 89-7 (4.70 g, 70%).

¹H NMR (300 MHz, DMSO-d₆, δ): 10.19 (s, 1H), 7.45 (d, J=9.0 Hz, 2H),7.24 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H),5.40-5.35 (m, 1H), 4.04-3.92 (m, 1H), 3.82-3.66 (m, 1H), 3.24-3.03 (m,2H), 1.99 (s, 3H).

Step 8

8-(4-Chlorophenoxy)-5-cyanochroman-3-yl acetate (Compound 89-8)

Compound 89-7 (0.24 g, 0.63 mmol) was dissolved in DMF (3.0 mL), andpotassium carbonate (0.10 g, 0.76 mmol) was added to the solution. Themixture was stirred at room temperature for one hour. Water was added tothe mixture. The organic layer was extracted with tert-butyl methylether, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=100/0→80/20) to obtain compound89-8 (0.16 g, 75%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.45-7.42 (m, 3H), 7.03-6.97 (m, 3H),5.32-5.30 (m, 1H), 4.32-4.16 (m, 2H), 3.38-3.33 (m, 1H), 2.99-2.94 (m,1H), 2.02 (s, 3H).

Step 9

5-(Aminomethyl)-8-(4-chlorophenoxy)chroman-3-yl acetate (Compound 89-9)

Compound 89-9 (0.12 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 89-8.

ESIMS m/z: [M+H]⁺ 348.

Step 10

5-(Acrylamidemethy)-8-(4-chlorophenoxy)chroman-3-yl acetate (Compound174)

Compound 174 (0.09 g, 71% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 89-9.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.48 (t, J=5.4 Hz, 1H), 7.34 (d, J=9.0 Hz,2H), 6.94 (d, J=8.4 Hz, 1H), 6.87-6.83 (m, 3H), 6.30 (dd, J=17.1, 10.2Hz, 1H), 6.13 (dd, J=17.1, 2.1 Hz, 1H), 5.63 (dd, J=9.9, 2.1 Hz, 1H),5.25 (br, 1H), 4.32-4.26 (m, 2H), 4.15-4.01 (m, 2H), 3.15-3.07 (m, 1H),2.84-2.73 (m, 1H), 2.01 (s, 3H);

ESIMS m/z: [M+H]⁺ 402.

Step 11

N-[{8-(4-Chlorophenoxy)-3-hydroxychroman-5-yl}methyl]acrylamide(Compound 175)

Compound 174 (0.27 g, 0.66 mmol) was dissolved in THF (2 mL), methanol(2 mL), and water (2 mL), and sodium hydroxide (0.04 g, 0.99 mmol) wasadded to the solution. The mixture was stirred at room temperature for 2hours. The mixture was concentrated under reduced pressure. Water and a2 mol/L aqueous hydrochloric acid solution were added to the residue.The mixture was extracted with dichloromethane, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=100/0→80/20) to obtain compound 175 (0.12 g, 46%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.45 (t, J=5.6 Hz, 1H), 7.33 (d, J=9.2 Hz,2H), 6.89 (d, J=8.0 Hz, 1H), 6.83-6.81 (m, 3H), 6.30 (dd, J=17.2, 10.4Hz, 1H), 6.13 (dd, J=17.2, 2.4 Hz, 1H), 5.62 (dd, J=10.0, 2.0 Hz, 1H),5.17 (d, J=4.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 2H), 4.03-3.96 (m, 2H),3.76-3.72 (m, 1H), 2.97-2.92 (m, 1H), 2.60-2.56 (m, 1H);

ESIMS m/z: [M+H]⁺ 360.

Example 90

Step 1

8-(4-Chlorophenoxy)-3-hydroxychromane-5-carbonitrile (Compound 90-1)

Compound 90-1 (0.30 g, 68%) was obtained in the same manner as step 11of example 89, using compound 89-8.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.41 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz,1H), 6.99 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 5.30 (d, J=3.6 Hz,1H), 4.17-4.00 (m, 2H), 3.99-3.96 (m, 1H), 3.17-3.11 (m, 1H), 2.82-2.77(m, 1H).

Step 2

8-(4-Chlorophenoxy)-2H-chromene-5-carbonitrile (Compound 90-2)

Compound 90-1 (0.25 g, 0.83 mmol) was dissolved in toluene (5.0 mL), andmethyl N-(triethylammoniumsulfonyl)carbamate (0.39 g, 1.65 mmol) wasadded to the solution. The mixture was stirred at 100° C. for 3 hours.The mixture was cooled to 0° C., and sodium hydride (0.074 g, 1.63 mmol)was added to the mixture. The mixture was stirred at 100° C. for 3hours. The mixture was cooled to 0° C., and water was added to themixture. The organic layer was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=80/20→50/50) to obtain compound 90-2 (0.075 g, 32%).

¹H NMR (300 MHz, DMSO-d₆, δ): 7.43-7.36 (m, 3H), 7.04-6.99 (m, 6.66 (d,J=10.2 Hz, 1H), 6.27-6.22 (m, 1H), 4.87-4.86 (m, 2H).

Step 3

{8(4-Chlorophenoxy)chroman-5-yl}methanamine (Compound 90-3)

Compound 90-3 (0.025 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 90-2.

ESIMS m/z: [M−16]⁺ 273.

Step 4

N-[{8-(4-Chlorophenoxy)chroman-5-yl}methyl]acrylamide (Compound 176)

Compound 176 (0.025 g, 31% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 90-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.44 (br, 1H), 7.32 (d, J=8.0 Hz, 2H),6.89-6.80 (m, 4H), 6.30 (dd, J=17.6, 10.4 Hz, 1H), 6.15-6.11 (m, 1H),5.63-5.61 (m, 1H), 4.29 (d, J=3.2 Hz, 2H), 4.03 (br, 2H), 2.72 (br, 2H),1.92 (br, 2H);

ESIMS m/z: [M+H]⁺ 344.

The following compound was synthesized in accordance with the synthesismethod of compound 152.

N-[{6-(4-Chlorophenoxy)chroman-4-yl}methyl]acrylamide (Compound 177)

ESIMS m/z: [M+H]⁺ 344.

ESIMS m/z: [M+H]⁺ 397.

Example 91

Step 1

2-Methoxy-8-{4-(trifluoromethyl)phenoxy}-7,8-dihydroquinolin-5(6H)-one(Compound 91-1)

Compound 37-2 (0.20 g, 0.59 mmol) was dissolved in methanol (0.6 mL),and sodium methoxide (37.9 mg, 0.70 mmol) was added to the solution. Themixture was stirred at 60° C. overnight. A saturated aqueous sodiumbicarbonate solution was added to the mixture. The organic layer wasextracted with ethyl acetate, washed with saturated saline, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure toobtain compound 91-1 (0.20 g) as a crude product, which was used as itis in the next reaction.

ESIMS m/z: [M+H]⁺ 338.

Step 2

2-Methoxy-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-amine(Compound 91-2)

Compound 91-2 (0.23 g) was obtained as a crude product in the samemanner as step 2 of example 3, using compound 91-1, and used as it is inthe next reaction.

ESIMS m/z: [M+H]⁺ 339.

Step 3

cis-N-[2-Methoxy-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 179)

Compound 179 (4.70 mg, 2.1% over three steps) was obtained in the samemanner as step 1 of example 76, using compound 91-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.56 (d, J=8.5 Hz, 3H), 7.28 (d, J=7.4 Hz,2H), 6.71 (d, J=8.5 Hz, 1H), 6.38 (dd, J=16.9, 1.3 Hz, 1H), 6.13 (dd,J=16.9, 10.2 Hz, 1H), 5.75 (br, 1H), 5.74 (dd, J=10.2, 1.3 Hz, 1H),5.38-5.32 (m, 2H), 3.80 (s, 3H), 2.36-2.29 (m, 1H), 2.17-2.09 (m, 3H).

ESIMS m/z: [M+H]⁺ 393.

Example 92

Step 1

2-[{2-(Dimethylamino)ethyl}(methyl)amino]-8-{4-(trifluoromethyl)phenoxy}-7,8-dihydroquinolin-5(6H)-one(Compound 92-1)

Compound 37-2 (0.10 g, 0.29 mmol) was dissolved in DMF (1.5 mL), andN1,N1,N2-trimethylethane-1,2-diamine (44.9 mg, 0.44 mmol) was added tothe solution. The mixture was stirred at 80° C. for 3 hours. The mixturewas cooled to room temperature, and concentrated under reduced pressure.The residue was purified by aminosilica gel column chromatography(hexane/ethyl acetate=70/30→40/60) to obtain compound 92-1 (88.4 mg,74%).

¹H NMR (400 MHz, CDCl₃, δ): 8.07 (d, J=9.0 Hz, 1H), 7.54 (d, J=8.5 Hz,2H), 7.25 (d, J=8.5 Hz, 2H), 6.52 (d, J=9.0 Hz, 1H), 5.45 (dd, J=5.4,3.6 Hz, 1H), 3.64-3.63 (m, 2H), 3.07 (s, 3H), 3.04-2.95 (m, 1H), 2.60(ddd, J=17.4, 6.2, 5.0 Hz, 1H), 2.52-2.36 (m, 4H), 2.20 (s, 6H).

ESIMS m/z: [M+H]⁺ 408.

Step 2

N2-{2-(Dimethylamino)ethyl}-N2-methyl-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinoline-2,5-diamine(Compound 92-2)

Compound 92-2 was obtained as a crude product in the same manner as step2 of example 17, using compound 92-1 (88.4 mg, 0.22 mmol), and used asit is in the next reaction.

ESIMS m/z: [M+H]⁺ 409.

Step 3

cis-N-(2-[{2-(Dimethylamino)ethyl}(methyl)amino]-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl)acrylamide(Compound 180)

Compound 180 (10.2 mg, 10% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 92-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.54 (d, J=9.0 Hz, 2H), 7.41 (d, J=8.5 Hz,1H), 7.25 (d, J=8.5 Hz, 2H), 6.47 (d, J=9.0 Hz, 1H), 6.35 (dd, J=17.0,1.2 Hz, 1H), 6.11 (dd, J=17.0, 10.3 Hz, 1H), 5.72 (br, 1H), 5.71 (dd,J=10.3, 1.2 Hz, 1H), 5.30-5.24 (m, 2H), 3.62-3.59 (m, 1H), 3.54-3.47 (m,1H), 2.97 (s, 3H), 2.37-2.03 (m, 6H), 2.18 (s, 6H).

ESIMS m/z: [M+H]⁺ 463.

Example 93

Step 1

2-Chloro-8-{(5,6-dichloropyridin-3-yl)oxy}-7,8-dihydro-6H-spiro[quinoline-5,2′-[1,3]dioxolane](Compound 93-1)

Compound 93-1 (0.20 g) was obtained as a crude product in the samemanner as step 4 of example 33, using compound 33-3 (0.10 g, 0.41 mmol)and 5,6-dichloropyridin-3-ol (70.0 mg, 0.41 mmol), and used as it is inthe next reaction.

¹H NMR (300 MHz, DMSO-d6, δ): 8.13 (d, J=2.7 Hz, 1H), 7.82 (d, J=8.4 Hz,1H), 7.67 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 5.30 (t, J=3.6 Hz,1H), 4.28-4.04 (m, 4H), 2.35-2.22 (m, 3H), 2.03-2.00 (m, 1H).

Step 2

2-Chloro-8-{(5,6-dichloropyridin-3-yl)oxy}-7,8-dihydroquinolin-5(6H)-one(Compound 93-2)

Compound 93-2 (0.18 g) was obtained as a crude product in the samemanner as step 5 of example 33, using compound 93-1, and used as it isin the next reaction.

¹H NMR (300 MHz, DMSO-d6, δ): 8.28 (d, J=8.4 Hz, 1H), 8.19 (d, J=2.4 Hz,1H), 7.76 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 5.15 (t, J=3.6 Hz,1H), 3.15-3.03 (m, 1H), 2.77-2.45 (m, 3H).

Step 3

2-Chloro-8-{(5,6-dichloropyridin-3-yl)oxy}-5,6,7,8-tetrahydroquinolin-5-amine(Compound 93-3)

Compound 93-3 (50.0 mg, 35% over three steps) was obtained in the samemanner as step 4 of example 1, using compound 93-2.

¹H NMR (400 MHz, DMSO-d6, δ): 8.23-8.22 (m, 1H), 8.16 (d, J=8.4 Hz,0.7H), 8.10-8.09 (m, 1H), 8.00 (d, J=8.4 Hz, 0.3H), 7.53-7.47 (m, 1H),5.63-5.62 (m, 0.3H), 5.60-5.56 (m, 0.7H), 3.98-3.95 (m, 0.3H), 3.83-3.78(m, 0.7H), 2.41-2.21 (m, 3H), 2.18-2.04 (m, 1H).

Step 4

cis-N-[2-Chloro-8-{(5,6-dichloropyridin-3-yl)oxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 181)

Compound 181 (0.22 g, 40%) was obtained in the same manner as step 5 ofexample 1, using compound 93-3 (0.48 mg, 0.14 mmol).

¹H NMR (300 MHz, CDCl3, δ): 8.14 (d, J=3.0 Hz, 1H), 7.74 (d, J=2.4 Hz,1H), 7.70 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.41 (dd, J=16.8,1.2 Hz, 1H), 6.16 (dd, J=17.1, 10.2 Hz, 1H), 5.82-5.76 (m, 2H),5.43-5.31 (m, 2H), 2.42-2.37 (m, 1H), 2.31-2.13 (m, 3H).

ESIMS m/z: [M+H]⁺ 400.

Example 94

Step 1

5-Oxo-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinoline-2-carbonitrile(Compound 94-1)

Compound 94-1 (65.2 mg, 75%) was obtained in the same manner as step 1of example 54, using compound 37-2 (90.0 mg, 0.26 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 8.50 (d, J=7.7 Hz, 1H), 7.85 (d, J=7.7 Hz,1H), 7.60 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 5.70 (t, J=3.4 Hz,1H), 3.21 (ddd, J=18.1, 13.1, 4.8 Hz, 1H), 2.80 (dt, J=18.1, 4.8 Hz,1H), 2.72-2.65 (m, 1H), 2.49-2.40 (m, 1H).

ESIMS m/z: [M+H]⁺ 333.

Step 2

5-Amino-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinoline-2-carbonitrile(Compound 94-2)

Compound 94-2 was obtained as a crude product in the same manner as step2 of example 3, using compound 94-1 (65.2 mg, 0.20 mmol), and used as itis in the next reaction.

Step 3

cis-N-[2-Cyano-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 182)

Compound 182 (20.4 mg, 27% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 94-2.

¹H NMR (400 MHz, CDCl3, δ): 7.90 (dd, J=8.1, 1.0 Hz, 1H), 7.66 (d, J=8.1Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.44 (dd,J=16.7, 1.0 Hz, 1H), 6.17 (dd, J=16.7, 10.3 Hz, 1H), 5.87 (d, J=9.0 Hz,1H), 5.81 (dd, J=10.3, 1.0 Hz, 1H), 5.51-5.44 (m, 2H), 2.50-2.46 (m,1H), 2.24-2.05 (m, 3H).

ESIMS m/z: [M+H]⁺ 388.

Example 95N-[(5R*,8S*)-2-Methyl-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 183)

Compound 242 (30.0 mg, 0.076 mmol) was dissolved in toluene (1.0 mL),and added to the solution were palladium acetate (1.7 mg, 7.60 μmol),trimethylboroxine (38.0 mg, 0.30 mmol),dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphate (7.1 mg,15.0 μmol), cesium carbonate (0.74 g, 0.23 mmol), and water (0.3 mL).The mixture was stirred at 100° C. overnight. The mixture was cooled toroom temperature, and added to the mixture were palladium acetate (1.7mg, 7.60 μmol), trimethylboroxine (19.0 mg, 0.15 mmol),dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphate (7.1 mg,15.0 μmol), and cesium carbonate (0.74 g, 0.23 mmol). The mixture wasagain stirred at 100° C. for 1.5 hours. The mixture was cooled to roomtemperature and filtered with Presep ((R); diatomaceous earth, granulartype M, 4.5 g/25 mL). The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(heptane/ethyl acetate=80/20→40/60) to obtain compound 183 (30.0 mg,quantitatively).

¹H NMR (400 MHz, CDCl3, δ): 7.60 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.5 Hz,2H), 7.20 (d, J=8.5 Hz, 2H), 7.14 (d, J=7.8 Hz, 1H), 6.40 (dd, J=17.1,1.3 Hz, 1H), 6.15 (dd, J=17.1, 10.3 Hz, 1H), 5.80 (br, 1H), 5.75 (dd,J=10.3, 1.3 Hz, 1H), 5.45 (t, J=2.5 Hz, 1H), 5.38 (dd, J=15.7, 9.0 Hz,1H), 2.54 (s, 3H), 2.44-2.38 (m, 1H), 2.18-2.11 (m, 1H), 2.07-2.02 (m,2H).

ESIMS m/z: [M+H]⁺ 377.

Example 96cis-N-[2-Methyl-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 184)

Compound 184 (18.2 mg, 64%) was obtained in the same manner as step 1 ofexample 95, using compound 76 (30.0 mg, 0.076 mmol).

¹H NMR (400 MHz, CDCl3, δ): 7.60 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.5 Hz,2H), 7.20 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.40 (dd, J=17.0,1.3 Hz, 1H), 6.15 (dd, J=17.0, 10.3 Hz, 1H), 5.79 (br, 1H), 5.75 (dd,J=10.3, 1.3 Hz, 1H), 5.45 (t, J=2.7 Hz, 1H), 5.38 (dd, J=16.2, 9.0 Hz,1H), 2.54 (s, 3H), 2.44-2.39 (m, 1H), 2.16-2.14 (m, 1H), 2.08-2.01 (m,2H),

ESIMS m/z: [M+H]⁺ 377.

Example 97cis-N-[2-Cyclopropyl-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 185)

Compound 185 (17.8 mg, 59%) was obtained in the same manner as step 1 ofexample 95, using compound 76 (30.0 mg, 0.076 mmol) and potassiumcyclopropyltrifluoroborate (55.9 mg, 0.38 mmol).

¹H NMR (400 MHz, CDCl3, δ): 7.56 (d, J=10.4 Hz, 2H), 7.53 (d, J=8.1 Hz,1H), 7.27 (d, J=10.4 Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.38 (dd, J=16.9,1.3 Hz, 1H), 6.14 (dd, J=16.9, 10.3 Hz, 1H), 5.79 (br, 1H), 5.74 (dd,J=10.3, L3 Hz, 1H), 5.37-5.33 (m, 2H), 2.36-2.35 (m, 1H), 2.20-2.14 (m,1H), 2.12-2.06 (m, 2H), 2.01-4.94 (m, 1H), 1.02-0.88 (m, 3H), 0.86-0.79(m, 1H).

ESIMS m/z: [M+H]⁺ 403.

Step 1

cis-N-[2-ethyl-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 186)

Compound 186 (7.5 mg, 25%) was obtained in the same manner as step 1 ofexample 95, using compound 76 (30.0 mg, 0.076 mmol) and ethylboronicacid (5.6 mg, 0.076 mmol).

¹H NMR (400 MHz, CDCl3, δ): 7.63 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.5 Hz,2H), 7.25 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.39 (dd, J=16.9,1.3 Hz, 1H), 6.15 (dd, J=16.9, 10.1 Hz, 1H), 5.80 (d, J=9.4 Hz, 1H),5.75 (dd, J=10.1, 1.3 Hz, 1H), 5.46 (t, J=2.5 Hz, 1H), 5.39 (dd, J=16.2,9.9 Hz, 1H), 2.80 (q, J=7.6 Hz, 2H), 2.44-2.39 (m, 1H), 2.20-2.14 (m,1H), 2.10-2.05 (m, 2H), 1.26 (t, J=7.6 Hz, 3H).

ESIMS m/z: [M+H]⁺ 391.

Example 99

Step 1

2-Chloro-8-{3-fluoro-4-(trifluoromethyl)phenoxy}-7,8-dihydro-6H-spiro[quinoline-5,2′-[1,3]dioxolane](Compound 99-1)

Compound 99-1 (0.13 g, 38%) was obtained in the same manner as step 4 ofexample 33, using compound 33-3 (0.20 g, 0.83 mmol) and3-fluoro-4-(trifluoromethyl)phenol (0.18 g, 0.99 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 7.84 (d, J=8.5 Hz, 1H), 7.51 (t, J=8.1 Hz,1H), 7.36 (d, J=8.5 Hz, 1H), 6.92 (d, J=10.3 Hz, 2H), 5.39 (t, J=3.4 Hz,1H), 4.29-4.14 (m, 3H), 4.11-4.08 (m, 1H), 2.32-2.27 (m, 3H), 2.01-1.96(m, 1H).

ESIMS m/z: [M+H]⁺ 404.

Step 2

2-Chloro-8-{3-fluoro-4-(trifluoromethyl)phenoxy}-7,8-dihydroquinolin-5(6H)-one(Compound 99-2)

Compound 99-2 (0.11 g, quantitatively) was obtained in the same manneras step 5 of example 33, using compound 99-1 (0.13 g, 0.32 mmol).

¹H NMR (400 MHz, CDCl3, δ): 8.31 (d, J=8.1 Hz, 1H), 7.54 (t, J=8.5 Hz,1H), 7.49 (d, J=8.1 Hz, 1H), 7.04-7.01 (m, 2H), 5.59 (t, J=3.6 Hz, 1H),3.11 (ddd, J=17.5, 12.1, 4.9 Hz, 1H), 2.74 (dt, J=17.5, 4.0 Hz, 1H),2.64-2.60 (m, 1H), 2.48-2.39 (m, 1H).

ESIMS m/z: [M+H]⁺ 360.

Step 3

2-Chloro-8-{3-fluoro-4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-amine(Compound 99-3)

Compound 99-3 (0.11 g) was obtained as a crude product in the samemanner as step 2 of example 3, using compound 99-2 (0.11 g, 0.32 mmol),and used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 361.

Step 4

cis-N-[2-Chloro-8-{3-fluoro-4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 187)

Compound 187 (33.3 mg, 25% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 99-3.

¹H NMR (400 MHz, CDCl3, δ): 7.71 (d, J=8.1 Hz, 1H), 7.53 (t, J=8.3 Hz,1H), 7.32 (d, J=8.1 Hz, 1H), 6.96-6.93 (m, 2H), 6.42 (dd, J=16.9, 1.3Hz, 1H), 6.16 (dd, J=16.9, 10.3 Hz, 1H), 5.79 (dd, J=10.3, 1.3 Hz, 1H),5.77 (d, J=9.0 Hz, 1H), 5.42-5.38 (m, 2H), 2.42-2.41 (m, 1H), 2.19-2.17(m, 1H), 2.08-2.02 (m, 2H).

ESIMS m/z: [M+H]⁺ 415.

Example 100

Step 1

2-Ethoxy-8-{4-(trifluoromethyl)phenoxy}-7,8-dihydro-6H-spiro[quinoline-5,2′-[1,3]dioxolane](Compound 100-1)

Compound 37-1 (0.20 g, 0.52 mmol) was dissolved in ethanol (5 mL), and a20% sodium ethoxide solution in ethanol (0.41 mL, 1.04 mmol) was addedto the solution. The mixture was stirred at 80° C. for a week. Water wasadded to the mixture. The organic layer was extracted with ethylacetate, washed with saturated saline, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to obtain compound100-1 (0.13 g) as a crude product, which was used as it is in the nextreaction.

¹H NMR (400 MHz, CDCl₃, δ): 7.71 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.8 Hz,2H), 7.23 (d, J=8.8 Hz, 2H), 6.70 (d, J=8.5 Hz, 1H), 5.37 (t, J=4.0 Hz,1H), 4.27-4.05 (m, 6H), 2.35-2.28 (m, 3H), 2.02-1.98 (m, 1H), 1.23 (t,J=7.2 Hz, 3H).

ESIMS m/z: [M+H]⁺ 396.

Step 2

2-Methoxy-8-{4-(trifluoromethyl)phenoxy}-7,8-dihydroquinolin-5(6H)-one(Compound 100-2)

Compound 100-2 (0.12 g) was obtained as a crude product in the samemanner as step 5 of example 33, using compound 100-1 (0.13 g, 0.33mmol), and used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 352.

Step 3

2-Ethoxy-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-amine(Compound 100-3)

Compound 100-3 (71.0 mg) was obtained as a crude product in the samemanner as step 4 of example 1, using compound 100-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 353.

Step 4

cis-N-[2-Ethoxy-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 188)

Compound 188 (25.6 mg, 31% in four stages) was obtained in the samemanner as step 3 of example 17, using compound 100-3.

¹H NMR (400 MHz, CDCl3, δ): 7.57-7.54 (m, 3H), 7.26 (d, J=8.5 Hz, 2H),6.68 (d, J=8.5 Hz, 1H), 6.38 (dd, J=17.1, 1.3 Hz, 1H), 6.13 (dd, J=17.1,10.3 Hz, 1H), 5.74 (dd, J=10.3, 1.3 Hz, 1H), 5.73 (br, 1H), 5.36 (t,J=3.6 Hz, 1H), 5.30 (dd, J=8.8, 6.1 Hz, 1H), 4.22-4.16 (m, 2H),2.34-2.26 (m, 1H), 2.15-2.07 (m, 3H), 1.27 (t, J=7.2 Hz, 3H).

ESIMS m/z: [M+H]⁺ 407.

Example 101

Step 1

2-Chloro-8-[{5-(trifluoromethyl)pyridin-2-yl}oxy]-7,8-dihydro-6H-spiro[quinoline-5,2′-[1,3]dioxolane](Compound 101-1)

Compound 101-1 (0.15 g, 47%) was obtained as a crude product in the samemanner as step 4 of example 33, using compound 33-3 (0.20 g, 0.83 mmol)and 5-(trifluoromethyl)pyridin-2-ol (0.16 g, 0.99 mmol), and used as itis in the next reaction.

¹H NMR (400 MHz, CDCl₃, δ): 8.47 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.78(dd, J=8.6, 2.5 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H),6.30 (t, J=4.5 Hz, 1H), 4.28-4.09 (m, 4H), 2.41-2.36 (m, 2H), 2.24-2.19(m, 1H), 2.01-1.97 (m, 1H).

ESIMS m/z: [M+H]⁺ 387.

Step 2

2-Chloro-8-[{5-(trifluoromethyl)pyridin-2-yl}oxy]-7,8-dihydroquinolin-5(6H)-one(Compound 101-2)

Compound 101-2 (0.13 g, 97%) was obtained in the same manner as step 5of example 33, using compound 101-1 (0.15 g, 0.39 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 8.49 (dd, J=1.8, 0.9 Hz, 1H), 8.31 (d, J=8.3Hz, 1H), 7.83 (dd, J=8.8, 1.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 6.87 (d,J=8.8 Hz, 1H), 6.54 (dd, J=4.9, 3.6 Hz, 1H), 3.01-2.97 (m, 1H),2.77-2.62 (m, 2H), 2.53-2.45 (m, 1H).

ESIMS m/z: [M+H]⁺ 343.

Step 3

2-Chloro-8-[{5-(trifluoromethyl)pyridin-2-yl}oxy]-5,6,7,8-tetrahydroquinolin-5-amine(Compound 101-3)

Compound 101-3 (0.14 g) was obtained as a crude product in the samemanner as step 2 of example 3, using compound 101-2 (0.13 g, 0.38 mmol),and used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 344.

Step 4

cis-N-(2-Chloro-8-[{5-(trifluoromethyl)pyridin-2-yl}oxy]-5,6,7,8-tetrahydroquinolin-5-yl)acrylamide(Compound 189)

Compound 189 (25.7 mg, 17%) was obtained in the same manner as step 3 ofexample 17, using compound 101-3.

¹H NMR (400 MHz, CDCl3, δ): 8.47 (s, 1H), 7.79 (dd, J=8.8, 2.5 Hz, 1H),7.69 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H),6.41 (dd, J=16.9, 1.0 Hz, 1H), 6.25 (t, J=3.6 Hz, 1H), 6.15 (dd, J=16.9,10.3 Hz, 1H), 5.82 (d, J=9.0 Hz, 1H), 5.77 (dd, J=10.3, 1.0 Hz, 1H),5.39 (td, J=9.5, 5.5 Hz, 1H), 2.49-2.45 (m, 1H), 2.20-2.11 (m, 2H),2.03-1.94 (m, 1H).

ESIMS m/z: [M+H]⁺ 398.

Example 102

Step 1

3-Chloro-7,8-dihydroquinolin-5(6H)-one (Compound 102-1)

To a cyclohexane-1,3-dione (0.824 g, 7.35 mmol) solution in THF (20 mL),a 1 mol/L potassium tert-butoxide/tetrahydrofuran solution (8.00 mL,8.00 mmol) was added dropwise at 0° C. After the mixture was stirred atroom temperature for 30 minutes, 2-chloro-N,N-dimethylaminotrimethyniumhexafluorophosphate (1.50 g, 4.89 mmol) was added to the mixture. Themixture was stirred at 50° C. for one hour. Next, ammonium acetate (1.70g, 22.05 mmol) was added to the mixture, and the mixture was stirred at100° C. for 1.5 hours. After the reaction liquid was concentrated underreduced pressure, ethyl acetate was added to the residue. The mixturewas washed with water and saturated saline and dried over anhydrousmagnesium sulfate. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=100/0→70/30) to obtain compound102-1 (257.4 mg, 29%).

¹H NMR (400 MHz, CDCl₃, δ): 8.64 (d, J=2.7 Hz, 1H), 8.24 (d, J=2.7 Hz,1H), 3.14 (t, J=6.3 Hz, 2H), 2.70 (dd, J=7.2, 5.9 Hz, 2H), 2.21 (m, 2H).

Step 2

3-Chloro-5,6,7,8-tetrahydroquinolin-5-ol (Compound 102-2)

To a methanol solution (10 mL) of compound 102-1 (322.6 mg, 1.776 mmol),sodium borohydride (160.0 mg, 4.230 mmol) was added in small portions at0° C. After the mixture was stirred at room temperature for 15 minutes,water was added to the mixture. The mixture was extracted withchloroform. After the extracted liquid was dried over anhydrousmagnesium sulfate, the residue was purified by silica gel columnchromatography (heptane/ethyl acetate=100/0→50/50) to obtain compound102-2 (296.7 mg, 91%).

¹H NMR (400 MHz, CDCl₃, δ): 8.25 (d, J=2.7 Hz, 1H), 7.80 (d, J=2.7 Hz,1H), 4.74 (m, 1H), 4.62 (br d, J=6.3 Hz, 1H), 2.83 (m, 2H), 2.05 (m,2H), 1.80 (m, 2H);

ESIMS m/z: [M+H]⁺ 184, 186.

Step 3

5-Azido-3-chloro-5,6,7,8-tetrahydroquinoline (Compound 102-3)

Compound 102-2 (296.7 mg, 1.616 mmol) was dissolved in a toluene (8mL)-tetrahydrofuran (2 mL) mixed solvent, and1,8-diazabicyclo[5.4.0]-7-undecene (0.370 mL, 2.455 mmol) anddiphenylphosphorylazide (0.530 mL, 2.459 mmol) were sequentially addedto the mixture. The mixture was stirred at room temperature for 2 hours.The reaction liquid was concentrated under reduced pressure. A saturatedaqueous sodium hydrogen carbonate was added to the residue, and themixture was extracted with chloroform. The extracted liquid was washedwith saturated saline and dried over anhydrous magnesium sulfate. Theresidue was purified by silica gel column chromatography (heptane/ethylacetate=100/0→80/20) to obtain compound 102-3 (337.0 mg, 100%).

¹H NMR (400 MHz, CDCl₃, δ): 8.43 (d, J=2.3 Hz, 1H), 7.64 (d, J=2.3 Hz,1H), 4.54 (m, 1H), 2.91 (m, 2H), 2.07 (m, 2H), 2.00-1.83 (m, 2H);

ESIMS m/z: [M+H]⁺ 209, 211.

Step 4

tert-Butyl (3-chloro-5,6,7,8-tetrahydroquinolin-5-yl)carbamate (Compound102-4)

In ethyl acetate (15 mL), 10% palladium/carbon (140 mg) was suspended,and the suspension was stirred under hydrogen atmosphere for 15 minutes.Compound 102-3 (447.8 mg, 2.146 mmol) and an ethyl acetate solution (2mL) of di-tert-butyl dicarbonate (937.0 mg, 4.290 mmol) were added tothe suspension. The mixture was stirred at room temperature for 30minutes. The reaction liquid was filtered using Celite®. The residueobtained by concentrating the filtrate was purified by silica gel columnchromatography (heptane/ethyl acetate=100/0→50/50) to obtain compound102-4 (296.1 mg, 49%).

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (br, 1H), 7.66 (br, 1H), 4.87 (br, 1H),4.77 (br, 1H), 2.89 (m, 2H), 2.10 (m, 1H), 1.94 (m, 2H), 1.71 (m, 1H),1.50 (s, 9H);

ESIMS m/z: [M+H]⁺ 283, 285.

Step 5

tert-Butyl (3-chloro-8-hydroxy-5,6,7,8-tetrahydroquinolin-5-yl)carbamate(Compound 102-5)

3-Chloroperoxybenzoic acid (300.0 mg, 1.738 mmol) was added to amethylene chloride solution (5 mL) of compound 102-4 (296.1 mg, 1.047mmol). The mixture was stirred at room temperature for one hour. Asaturated aqueous sodium hydrogen carbonate solution was added to thereaction liquid, and the mixture was extracted with chloroform. Theextracted liquid was washed with a saturated aqueous sodium thiosulfatesolution and dried over anhydrous magnesium sulfate to obtain N-oxide(373.2 mg), N-Oxide obtained was dissolved in methylene chloride (3 mL).Trifluoroacetic anhydride (0.400 mL, 2.83 mmol) was added to thesolution at 0° C. The mixture was stirred at 0° C. for 20 minutes, andthen at room temperature for 16 hours. A 4 N aqueous sodium hydroxidesolution (2 mL, 8 mmol) was added to the mixture at 0° C. The mixturewas stirred at room temperature for 40 minutes. A 2 N aqueoushydrochloric acid solution was added dropwise to the mixture undercooling at 0° C. pH was adjusted to 2-3, and the mixture was extractedwith chloroform. The extracted liquid was washed with saturated salineand dried over anhydrous magnesium sulfate. The residue was purified bysilica gel column chromatography (chloroform/methanol=100/0→85/15) toobtain compound 102-5 (122.5 mg, 39%).

¹H NMR (400 MHz, CDCl₃, cis/trans-diastereo mixture, b): 8.10 (d, J=1.8Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.65 (br, 1H), 7.31 (br, 1H), 5.54 (d,J=9.1 Hz, 1H), 5.38 (d, J=9.5 Hz, 1H), 4.89 (m, 1H), 4.82 (m, 2H), 4.65(m, 3H), 2.85-2.65 (m, 2H), 2.32 (m, 1H), 2.11-1.95 (m, 3H), 1.81 (m,1H), 1.68 (m, 1H), 1.49 (s, 18H);

ESIMS m/z: [M+H]⁺ 299, 301.

Step 6

tert-Butyl(3-chloro-8-(4-(trifluoromethyl)phenoxy)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate(Compound 102-6)

To a tetrahydrofuran solution (4 mL) of compound 102-5 (122.5 mg, 0.410mmol), 4-(trifluoromethyl)phenol (140 mg, 0.864 mmol),triphenylphosphine (250 mg, 0.953 mmol), and a 2.2 mol/L diethylazodicarboxylate/toluene solution (0.400 mL, 0.880 mmol) weresequentially added. The mixture was stirred at room temperature for 2hours. After the reaction liquid was concentrated under reducedpressure, the residue was purified by silica gel column chromatography(heptane/ethyl acetate=100/0→70/30) to obtain compound 102-6 (182.0 mg,100%).

¹H NMR (400 MHz, CDCl₃, cis/trans-diastereo mixture, δ): 8.51 (m, 2H),7.80 (m, 2H), 7.52 (m, 4H), 7.10 (m, 4H), 5.47 (m, 2H), 5.01-4.85 (m,3H), 3.75 (m, 1H), 2.38 (m, 2H), 2.21 (m, 2H), 2.12 (m, 1H), 1.99 (m,2H), 1.85 (m, 1H), 1.52 (s, 9H), 1.50 (s, 9H);

ESIMS m/z: [M+H]⁺ 443, 445.

Step 7

N-((5R*,8S*)-3-Chloro-8-(4-(trifluoromethyl)phenoxy)-5,6,7,8-tetrahydroquinolin-5-yl)acrylamide(Compound 190)

Trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to a methylenechloride solution (2 mL) of compound 102-6 (191.5 mg, 0.432 mmol). Thesolution was stirred at room temperature for one hour. After thereaction liquid was concentrated under reduced pressure, the residue wasdissolved in methylene chloride (2 mL). Triethylamine (0.150 mL, 1.076mmol) and acryloyl chloride (0.100 mL, 1.231 mmol) were added dropwiseto the solution. The mixture was stirred at room temperature for 30minutes. The reaction liquid was poured onto a 1 N aqueous hydrochloricacid solution and the mixture was extracted with chloroform. Theextracted liquid was washed with saturated saline and dried overanhydrous magnesium sulfate. The residue was purified by silica gelcolumn chromatography (heptane/ethyl acetate=100/0→55/45) to obtaincompound 190 (cis isomer, 24.8 mg, 15%, and the trans isomer, 17.0 mg,9.9%).

¹H NMR (400 MHz, CDCl₃, δ): 8.49 (d, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz,1H), 7.56 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.42 (dd, J=16.8,1.4 Hz, 1H), 6.19 (dd, J=16.8, 10.4 Hz, 1H), 6.08 (d, J=9.5 Hz, 1H),5.78 (dd, J=10.4, 1.4 Hz, 1H), 5.47 (br t, J=2.3 Hz, 1H), 5.37 (m, 1H),2.46-2.35 (m, 1H), 2.18-2.00 (m, 3H);

ESIMS m/z: [M+H]⁺ 397, 399.

Example 103

Step 1

2-{4-(Trifluoromethyl)phenoxy}-7,8-dihydroquinolin-5(6H)-one (Compound103-1)

Commercially available 2-chloro-7,8-dihydroquinolin-5(6H)-one (0.20 g,1.10 mmol) was dissolved in DMF (5.5 mL), and cesium carbonate (0.72 g,2.20 mmol) and 4-(trifluoromethyl)phenol (0.72 g, 1.65 mmol) were addedto the solution. The mixture was subjected to a reaction at atemperature of 120° C. for 30 minutes using a microwave reactormanufactured by Biotage. Water was added to the mixture. The organiclayer was extracted with ethyl acetate, washed with saturated saline,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(heptane/ethyl acetate=90/10→60/40) to obtain compound 1034 (0.23 g,68%).

¹H NMR (400 MHz, CDCl3, δ): 8.32 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.6 Hz,2H), 7.29 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 2.96 (t, J=6.1 Hz,2H), 2.65 (t, J=6.6 Hz, 2H), 2.15 (tt, J=6.6, 6.1 Hz, 2H).

ESIMS m/z: [M+H]⁺ 308.

Step 2

2-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-amine(Compound 103-2)

Compound 103-2 was obtained as a crude product in the same manner asstep 2 of example 3, using compound 103-1 (0.23 g, 0.75 mmol), and usedas it is in the next reaction.

ESIMS m/z: [M+H]⁺ 309.

Step 3

N-[2-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compound 191)

Compound 191 (71.4 mg, 26%) was obtained in the same manner as step 3 ofexample 17, using compound 103-2.

¹H NMR (400 MHz, CDCl3, δ): 7.65 (d, J=8.1 Hz, 1H), 7.62 (d, J=8.7 Hz,2H), 7.20 (d, J=8.7 Hz, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.37 (dd, J=17.0,1.1 Hz, 1H), 6.10 (dd, J=17.0, 10.3 Hz, 1H), 5.72 (dd, J=10.3, 1.1 Hz,1H), 5.70 (d, J=8.5 Hz, 1H), 5.32 (dd, J=14.8, 6.3 Hz, 1H), 2.88-2.73(m, 2H), 2.12-2.08 (m, 1H), 1.91-1.83 (m, 3H).

ESIMS m/z: [M+H]⁺ 363.

Example 104

Step 1

5-[(4,4-Difluorocyclohexyl)methoxy]pyridin-3-amine (Compound 192)

Compound 104-1 (78.0 mg, 44%) was obtained in the same manner as step 4of example 33, using 4,4-difluorocyclohexanemethanol (110 mg, 0.733mmol) and 3-amino-5-hydroxypiperidine (161 mg, 1.47 mmol).

¹H NMR (400 MHz, CDCl₃, δ): 7.73 (d, J=1.8 Hz, 2H), 6.52-6.48 (m, 1H),3.82 (d, J=5.9 Hz, 2H), 3.67 (br, 2H), 2.22-2.08 (m, 2H), 1.99-1.66 (m,5H), 1.50-1.35 (m, 2H).

ESIMS m/z: [M+H]⁺ 243.

Step 2

Compound 192 (28.0 mg, yield 29%) was obtained in the same manner as instep 5 of example 1, using compound 104-1 (78.0 mg, 0.322 mmol) obtainedin step 1.

¹H NMR (400 MHz, CDCl₃, δ): 8.09-8.05 (m, 3H), 7.38 (br, 1H), 6.48 (dd,J=16.8, 0.9 Hz, 1H), 6.26 (dd, J=16.8, 10.4 Hz, 1H), 5.85 (dd, J=10.2,1.1 Hz, 1H), 3.88 (d, J=6.3 Hz, 2H), 2.22-2.09 (m, 2H), 2.01-1.67 (m,5H), 1.52-1.36 (m, 2H).

ESIMS m/z: [M+H]⁺ 297.

The following compound was synthesized in accordance with the synthesismethod of compound 95.

N-(5-{[4-(Trifluoromethyl)pyrimidin-2-yl]oxy}pyridin-3-yl)acrylamide(Compound 193)

ESIMS m/z: [M+H]⁺ 311.

The following compound was synthesized in accordance with the synthesismethod of compound 192.

N-{5-[(4,4-Difluorocyclohexyl)oxy]pyridin-3-yl}acrylamide (Compound 194)

ESIMS m/z: [M+H]⁺ 283.

The following compounds were synthesized in accordance with thesynthesis method of compound 137.

N-([8-{(4,4-Difluorocyclohexyl)methoxy}quinolin-5-yl]methyl)acrylamide(Compound 195)

ESIMS m/z: [M+H]⁺ 361.

N-{(8-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]quinolin-5-yl)methyl}acrylamide(Compound 197)

ESIMS m/z: [M+H]⁺ 374.

N-{(8-[{5-(Trifluoromethyl)pyrazin-2-yl}oxy]quinolin-5-yl)methyl}acrylamide(Compound 198)

ESIMS m/z: [M+H]⁺ 375.

Example 105

Step 1

8-[{2-(Trifluoromethyl)pyrimidin-5-yl}oxy]quinoline-5-carbonitrile(Compound 105-1)

Compound 105-1 (0.059 g, 66%) was obtained in the same manner as step 2of example 50, using compound 54-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.99 (dd, J=4.1, 1.8 Hz, 1H), 8.65 (dd,J=8.6, 1.8 Hz, 1H), 8.59 (s, 2H), 8.06 (d, J=8.2 Hz, 1H), 7.74 (dd,J=8.6, 4.1 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H);

ESIMS m/z: [M+H]⁺ 317.

Step 2

(8-[{2-(Trifluoromethy)pyrimidin-5-yl}oxy]quinolin-5-yl)methanamine(Compound 105-2)

Compound 105-2 (0.063 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 105-1.

ESIMS m/z: [M+H]⁺ 321.

Step 3

N-{(8-[{2-(Trifluoromethyl)pyrimidin-5-yl}oxy]quinolin-5-yl)methyl}acrylamide(Compound 196)

Compound 196 (0.025 g, 36% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 105-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.88 (dd, J=4.3, 1.5 Hz, 1H), 8.54 (dd,J=8.5, 1.5 Hz, 1H), 8.49 (s, 2H), 7.60-7.54 (m, 2H), 7.47 (d, J=7.6 Hz,1H), 6.40 (dd, J=17.0, 1.2 Hz, 1H), 6.11 (dd, J=17.0, 10.3 Hz, 1H), 5.87(br, 1H), 5.74 (dd, J=10.3, 1.2 Hz, 1H), 5.03 (d, J=5.8 Hz, 2H);

ESIMS m/z: [M+H]⁺ 375.

Example 106

Step 1

3-Iodo-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile (Compound106-1)

Compound 59-1 (0.10 g, 0.32 mmol) was dissolved in acetonitrile (5.0mL), and iodine (0.12 g, 0.48 mmol) and tert-butyl hydroperoxide (0.44mL, 3.18 mmol) were added to the solution. The mixture was stirred at80° C. for five days. The mixture was cooled to room temperature, andsodium thiosulfate was added to the mixture. The organic layer wasextracted with ethyl acetate, washed with saturated saline, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(heptane/ethyl acetate=80/20→50/50) to obtain compound 106-1 (0.051 g,36%).

¹H NMR (400 MHz, CDCl₃, δ): 9.21 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.8 Hz,1H), 7.89 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.27-7.26 (m, 2H),7.07 (d, J=8.3 Hz, 1H).

Step 2

3-Methyl-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile(Compound 106-2)

Compound 106-1 (0.06 g, 0.14 mmol) was dissolved in toluene (1.0 mL) andwater (0.25 mL), and added to the solution were cesium carbonate (0.22g, 0.68 mmol), trimethylboroxine (0.095 mL, 0.68 mmol),2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (0.013 g, 0.027mmol), and palladium acetate (0.003 g, 0.014 mmol). The mixture wasstirred under argon atmosphere at 100° C. for 0.5 hours. The mixture wasfiltered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25mL), and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (heptane/ethylacetate=80/20→50/50) to obtain compound 106-2 (0.044 g, 98%).

¹H NMR (400 MHz, CDCl₃, δ): 8.93 (s, 1H), 8.34 (s, 1H), 7.86 (d, J=8.1Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.27-7.26 (m, 2H), 7.00 (d, J=8.1 Hz,1H), 2.65 (s, 3H).

Step 3

[3-Methyl-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methanamine(Compound 106-3)

Compound 106-3 (0.039 g, 96%) was obtained in the same manner as step 2of example 57, using compound 106-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.80 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 7.57(d, J=8.8 Hz, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.09(d, J=8.8 Hz, 2H), 4.31 (s, 2H), 2.57 (s, 3H).

Step 4

N-([3-Methyl-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 199)

Compound 199 (0.032 g, 80%) was obtained in the same manner as step 3 ofexample 17, using compound 106-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.80 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 7.58(d, J=9.3 Hz, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.11-7.10 (m, 3H), 6.38 (dd,J=17.0, 1.1 Hz, 1H), 6.10 (dd, J=17.0, 10.2 Hz, 1H), 5.80 (br, 1H), 5.71(dd, J=10.2, 1.1 Hz, 1H), 4.94 (d, J=5.4 Hz, 2H), 2.55 (s, 3H);

ESIMS m/z: [M+H]⁺ 387.

Example 107

Step 1

3-Iodo-8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinoline-5-carbonitrile(Compound 107-1)

Compound 107-1 (0.22 g, 91%) was obtained in the same manner as step 1of example 106, using compound 62-1.

¹H NMR (400 MHz, CDCl₃, δ): 9.16 (d, J=2.0 Hz, 1H), 8.98 (d, J=2.0 Hz,1H), 8.57 (d, J=2.5 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.8 Hz,1H), 7.52 (dd, J=8.4, 2.5 Hz, 1H), 7.26-7.25 (m, 1H).

Step 2

3-Methyl-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]quinoline-5-carbonitrile(Compound 107-2)

Compound 107-2 (0.040 g, 90%) was obtained in the same manner as step 2of example 106, using compound 107-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.89 (d, J=2.4 Hz, 1H), 8.57 (d, J=2.4 Hz,1H), 8.36 (s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.51(dd, J=8.7, 2.7 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 2.65 (s, 3H).

Step 3

(3-Methyl-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]quinolin-5-yl)methanamine(Compound 107-3)

Compound 107-3 (0.065 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 107-2.

ESIMS m/z: [M+H]⁺ 334.

Step 4

N-{(3-Methyl-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]quinolin-5-yl)methyl}acrylamide(Compound 200)

Compound 200 (0.025 g, 54% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 107-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.72 (s, 1H), 8.43 (d, J=2.7 Hz, 1H), 8.20(s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.30 (dd,J=8.5, 2.7 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 6.37 (dd, J=17.1, 1.3 Hz,1H), 6.19 (br, 1H), 6.12 (dd, J=17.1, 10.3 Hz, 1H), 5.70 (d, J=10.3 Hz,1H), 4.94 (d, J=5.4 Hz, 2H), 2.53 (s, 3H);

ESIMS m/z: [M+H]⁺ 388.

Example 108

Step 1

5-Bromo-8-fluoro-4-methylquinoline (Compound 108-1)

5-Bromo-2-fluoroaniline (0.20 g, 1.05 mmol) was dissolved in toluene(3.0 mL), and a 6 mol/L aqueous hydrochloric acid solution (0.53 mL,3.16 mmol) and methyl vinyl ketone (0.17 mL, 2.11 mmol) were added tothe solution. The mixture was stirred at 120° C. for 1.5 hours. Themixture was left to cool to room temperature, and water was added to themixture. The aqueous layer was washed with ethyl acetate. A 2 mol/Laqueous sodium hydroxide solution was added to the aqueous layer, andthe aqueous layer was extracted with ethyl acetate, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (heptane/ethylacetate=90/10→80/20) to obtain compound 108-1 (0.040 g, 16%).

¹H NMR (400 MHz, CDCl₃, δ): 8.79 (d, J=4.2 Hz, 1H), 7.81 (dd, J=8.3, 5.4Hz, 1H), 7.34 (d, J=4.2 Hz, 1H), 7.23 (t, J=9.0 Hz, 1H), 3.14 (s, 3H).

Step 2

8-Fluoro-4-methylquinoline-5-carbonitrile (Compound 108-2)

Compound 108-2 (0.047 g, 48%) was obtained in the same manner as step 1of example 54, using compound 108-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.90 (d, J=4.4 Hz, 1H), 8.01 (dd, J=8.1, 5.1Hz, 1H), 7.49-7.42 (m, 2H), 3.12 (s, 3H).

Step 3

4-Methyl-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile(Compound 108-3)

Compound 108-3 (0.051 g, 66%) was obtained in the same manner as step 2of example 50, using compound 108-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.90 (d, J=4.4 Hz, 1H), 7.93 (d, J=8.3 Hz,1H), 7.70 (d, J=9.3 Hz, 2H), 7.44 (d, J=4.4 Hz, 1H), 7.26-7.22 (m, 2H),7.06 (d, J=8.3 Hz, 1H), 3.14 (s, 3H).

Step 4

[4-Methyl-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methanamine(Compound 108-4)

Compound 108-4 (0.043 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 108-3.

Step 5

N-([4-Methyl-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 201)

Compound 201 (0.013 g, 22% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 108-4.

¹H NMR (400 MHz, CDCl₃, δ): 8.71 (d, J=4.4 Hz, 1H), 7.57 (d, J=8.8 Hz,2H), 7.47 (d, J=7.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.16 (d, J=7.8 Hz, 1H),7.05 (d, J=8.8 Hz, 2H), 6.37 (d, J=17.1 Hz, 1H), 6.12 (dd, J=17.1, 10.2Hz, 1H), 6.02 (br, 1H), 5.69 (d, J=10.2 Hz, 1H), 5.04 (d, J=4.9 Hz, 2H),2.92 (s, 3H);

ESIMS m/z: [M+H]⁺ 387.

Example 109

Step 1

8-[{4-(Trifluoromethyl)phenyl}thio]quinoline-5-carbonitrile (Compound109-1)

Compound 109-1 (0.40 g, 42%) was obtained in the same manner as step 2of example 50, using compound 54-1.

ESIMS m/z: [M+H]⁺ 331.

Step 2

(8-[{4-(Trifluoromethyl)phenyl}thio]quinolin-5-yl)methanamine (Compound109-2)

Compound 109-2 (0.20 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 109-1.

ESIMS m/z: [M+H]⁺ 335.

Step 3

N-{(8-[{4-(Trifluoromethyl)phenyl}thio]quinolin-5-yl)methyl}acrylamide(Compound 202)

Compound 202 (0.10 g, 34% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 109-2.

¹H NMR (400 MHz, DMSO-d6, δ): 8.96 (dd, J=4.0, 1.6 Hz, 1H), 8.67 (t,J=5.6 Hz, 1H), 8.61 (dd, J=8.8, 1.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H),7.70-7.67 (m, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.37(d, J=7.6 Hz, 1H), 6.29-6.22 (m, 1H), 6.17-6.12 (m, 1H), 5.62 (dd,J=10.0, 2.4 Hz, 1H), 4.80 (d, J=5.6 Hz, 2H);

ESIMS m/z: [M+H]⁺ 389.

Example 110

Step 1

8-[{4-(Trifluoromethyl)phenyl}amino]quinoline-5-carbonitrile (Compound110-1)

Compound 110-1 (0.25 g, 46%) was obtained in the same manner as step 2of example 50, using compound 54-1.

ESIMS m/z: [M+H]⁺ 314.

Step 2

5-(Aminomethyl)-N-{4-(trifluoromethyl)phenyl}quinolin-8-amine (Compound110-2)

Compound 110-2 (0.20 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 110-1.

ESIMS m/z: [M+H]⁺ 318.

Step 3

N-{(8-[{4-(Trifluoromethyl)phenyl}amino]quinolin-5-yl)methyl}acrylamide(Compound 203)

Compound 203 (0.020 g, 8% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 110-2.

¹H NMR (400 MHz, DMSO-d6, δ): 9.13 (s, 1H), 8.92 (d, J=3.9 Hz, 1H),8.60-8.51 (m, 2H), 7.69-7.46 (m, 7H), 6.30-6.21 (m, 1H), 6.18-6.11 (m,1H), 6.62 (dd, J=9.6, 2.4 Hz, 1H), 4.75 (d, J=5.4 Hz, 2H);

ESIMS m/z: [M+H]⁺ 372.

Example 111N-{(8-[{4-(Trifluoromethyl)phenyl}sulfonyl]quinolin-5-yl)methyl}acrylamide(Compound 204)

Compound 202 (0.050 g, 0.12 mmol) was dissolved in dichloroethane (10mL), and Oxone (0.29 g, 1.93 mmol) was added to the solution. Themixture was stirred at 80° C. for 12 hours. The mixture was cooled toroom temperature, and water (10 mL) was added to the mixture. Theorganic layer was extracted with dichloromethane, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=80/20→40/60) to obtain compound 204 (0.050 g, 85%).

¹H NMR (300 MHz, DMSO-d₆, δ): 8.91 (d, J=3.3 Hz, 1H), 8.80-7.79 (m, 1H),8.69-8.64 (m, 2H), 8.27 (d, J=7.8 Hz, 2H), 7.93 (d, J=8.1 Hz, 2H), 7.78(d, J=7.5 Hz, 1H), 7.66 (dd, J=8.4, 4.2 Hz, 1H), 6.33-6.24 (m, 1H),6.19-6.13 (m, 1H), 5.68-5.64 (m, 1H), 4.90 (d, J=5.7 Hz, 2H);

ESIMS m/z: [M+H]⁺ 421.

Example 112

Step 1

8-[Methyl{4-(trifluoromethyl)phenyl}amino]quinoline-5-carbonitrile(Compound 112-1)

Compound 112-1 (0.12 g, 21%) was obtained in the same manner as step 2of example 50, using compound 54-1.

¹H NMR (400 MHz, CDCl₃, δ): 9.12 (dd, J=4.4, 1.6 Hz, 1H), 8.94 (dd,J=4.4 Hz, 2.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.74-7.71 (m, 1H), 7.62(d, J=8.0 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.58(s, 3H).

Step 2

5-(Aminomethyl)-N-methyl-N-{4-(trifluoromethyl)phenyl}quinolin-8-amine(Compound 112-2)

Compound 112-2 (0.10 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 112-1.

ESIMS m/z: [M+H]⁺ 332.

Step 3

N-{(8-[Methyl{4-(trifluoromethyl)phenyl}amino]quinolin-5-yl)methyl}acrylamide(Compound 205)

Compound 205 (0.030 g, 21% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 112-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.91 (dd, J=4.4, 1.6 Hz, 1H), 8.48 (dd,J=8.8, 1.6 Hz, 1H), 7.59-7.47 (m, 3H), 7.35 (d, J=8.8 Hz, 2H), 6.68 (d,J=8.8 Hz, 2H), 6.39 (dd, J=17.2, 1.2 Hz, 1H), 6.10 (dd, J=16.8, 10.4 Hz,1H), 5.83-5.82 (m, 1H), 5.72 (dd, J=10.4, 1.2 Hz, 1H), 5.01 (d, J=5.6Hz, 2H), 3.48 (s, 3H);

ESIMS m/z: [M+H]⁺ 386.

Example 113

Step 1

(5-Bromoquinolin-8-yl){4-(trifluoromethyl)phenyl}methanol (Compound113-1)

Magnesium (turnings) (0.08 g, 3.41 mmol) was dissolved in THF (10 mL),and iodine (10 mg) was added to the solution. The mixture was stirred atroom temperature for 5 minutes. 1-Bromo-4-(trifluoromethyl)benzene (0.38g, 1.70 mmol) was added to the mixture. The mixture was stirred at roomtemperature for 45 minutes. Thereafter, the mixture was cooled to and aTHF (5.0 mL) solution of 5-bromoquinoline-8-carboaldehyde (0.20 g, 0.85mmol) was added to the mixture. The mixture was stirred at 0° C. for 30minutes. A saturated aqueous ammonium chloride solution was added to themixture. The organic layer was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=90/10−>70/30) to obtain compound 113-1 (0.15 g, 46%).

¹H NMR (400 MHz, DMSO-d6, δ): 9.02 (dd, J=4.0, 1.6 Hz, 1H), 8.53 (dd,J=8.8, 1.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0 Hz, 1H),7.73-7.70 (m, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.00(d, J=4.4 Hz, 1H), 6.26 (d, J=4.4 Hz, 1H).

Step 2

8-[Hydroxy{4-(trifluoromethyl)phenyl}methyl]quinoline-5-carbonitrile(Compound 113-2)

Compound 113-2 (0.020 g, 58%) was obtained in the same manner as step 1of example 54, using compound 113-1.

¹H NMR (300 MHz, CDCl₃, δ): 8.99 (d, J=3.9 Hz, 1H), 8.61 (d, J=8.4 Hz,1H), 7.95 (d, J=7.5 Hz, 1H), 7.70-7.65 (m, 1H), 7.63-7.57 (m, 5H), 6.55(d, J=6.6 Hz, 1H), 6.04 (d, J=6.9 Hz, 1H).

Step 3

{5-(Aminomethyl)quinolin-8-yl}{4-(trifluoromethyl)phenyl}methanol(Compound 113-3)

Compound 113-3 (0.025 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 113-2.

¹H NMR (300 MHz, DMSO-d6, δ): 8.93 (d, J=3.6 Hz, 1H), 8.59 (d, J=8.4 Hz,1H), 7.87 (d, J=7.5 Hz, 1H), 7.67-7.53 (m, 6H), 7.01 (br, 1H), 6.17 (br,1H), 4.18 (s, 2H).

Step 4

N-{(8-[Hydroxy{4-(trifluoromethyl)phenyl}methyl]quinolin-5-yl)methyl}acrylamide(Compound 206)

Compound 206 (0.13 g, 51%) was obtained in the same manner as step 1 ofexample 76, using compound 113-3.

¹H NMR (400 MHz, DMSO-d6, δ): 8.96 (dd, J=4.0, 1.2 Hz, 1H), 8.61 (t,J=5.6 Hz, 1H), 8.52 (dd, J=8.8, 1.6 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H),7.66 (d, J=8.0 Hz, 2H), 7.67-7.56 (m, 4H), 7.01 (d, J=4.4 Hz, 1H),6.27-6.11 (m, 3H), 5.61 (dd, J=10.0, 2.4 Hz, 1H), 4.86-4.72 (m, 2H);

ESIMS m/z: [M+H]⁺ 387.

Example 114

Step 1

Triphenyl{4-(trifluoromethyl)benzyl}phosphonium bromide (Compound 114-1)

In toluene (10 mL), 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.00 g,4.18 mmol) was dissolved, and triphenylphosphine (1.64 g, 6.27 mmol) wasadded to the solution. The mixture was refluxed for 8 hours. The mixturewas cooled to room temperature. The precipitated solid was filtered offand washed with hexane to obtain compound 114-1 (1.75 g, 99%).

ESIMS m/z: [M+H]⁺ 422.

Step 2

(E)-5-Bromo-8-{4-(trifluoromethyl)styryl}quinoline (Compound 114-2)

Compound 114-1 (1.90 g, 4.51 mmol) was dissolved in THF (20 mL), and themixture was cooled to −78° C. Potassium tert-butoxide (1.01 g, 9.02mmol) was added to the mixture, and the mixture was stirred under argonatmosphere at −30° C. for 30 minutes. 5-Bromoquinoline-8-carboaldehyde(1.17 g, 4.96 mmol) was added to the mixture. The mixture was stirred atroom temperature for one hour. Water (10 mL) was added to the mixture.The organic layer was extracted with ethyl acetate, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=80/20→40/60) to obtain compound 114-2 (1.20 g, 70%).

ESIMS m/z: [M+H]⁺ 378.

Step 3

(E)-8-{4-(Trifluoromethyl)styryl}quinoline-5-carbonitrile (Compound114-3)

Compound 114-3 (0.80 g, 78%) was obtained in the same manner as step 1of example 54, using compound 114-2.

ESIMS m/z: [M+H]⁺ 325.

Step 4

(E)-[8-{4-(Trifluoromethyl)styryl}quinolin-5-yl]methanamine (Compound114-4)

Compound 114-4 (0.10 g) was obtained as a crude product in the samemanner as step 3 of example 54, using compound 114-3.

ESIMS m/z: [M+H]⁺ 329.

Step 5

(E)-N-([8-{4-(Trifluoromethyl)styryl}quinolin-5-yl]methyl)acrylamide(Compound 207)

Compound 207 (0.040 g, 22% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 114-4.

¹H NMR (400 MHz, DMSO-d6, δ): 8.97 (dd, J=4.0, 1.6 Hz, 1H), 8.65 (t,J=5.2 Hz, 1H), 8.57 (dd, J=8.4, 1.6 Hz, 1H), 7.66-7.63 (m, 1H),7.58-7.52 (m, 3H), 7.46 (d, J=7.2 Hz, 1H), 7.38-7.35 (m, 3H), 6.90 (d,J=12.4 Hz, 1H), 6.30-6.23 (m, 1H), 6.17-6.12 (m, 1H), 5.62 (dd, J=10.0,2.4 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H);

ESIMS m/z: [M+H]⁺ 383.

Example 115N-([8-{4-(Trifluoromethyl)benzoyl}quinolin-5-yl]methyl)acrylamide(Compound 208)

Compound 206 (0.20 g, 0.52 mmol) was dissolved in dichloromethane (10mL), and pyridinium chlorochromate (0.22 g, 1.03 mmol) was added to thesolution. The mixture was stirred at room temperature for 3 hours. Themixture was filtered with Celite®, and the filtrate was washed withdichloromethane (20 mL). The organic layer was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=80/20→20/80) to obtain compound 208(0.055 g, 24%).

¹H NMR (400 MHz, DMSO-d6, δ): 8.79-8.77 (m, 2H), 8.66 (dd, J=8.4, 1.2Hz, 1H), 7.88-7.81 (m, 5H), 7.68 (d, J=7.2 Hz, 1H), 7.64-7.61 (m, 1H),6.31 (dd, J=16.8, 10.0 Hz, 1H), 6.18 (dd, J=17.2, 2.4 Hz, 1H), 5.66 (dd,J=10.0, 2.4 Hz, 1H), 4.92 (d, J=5.6 Hz, 2H);

ESIMS m/z: [M+H]⁺ 385.

Example 116

Step 1

[8-{4-(Trifluoromethyl)phenethyl}quinolin-5-yl]methanamine (Compound116-1)

Compound 114-4 (0.05 g, 1.15 mmol) was dissolved in ethanol (20 mL), and10% palladium carbon (0.05 g) was added to the solution. The mixture wasstirred under hydrogen atmosphere at room temperature for 2 hours. Themixture was filtered with Celite®. The filtrate was concentrated underreduced pressure to obtain compound 116-1 (0.05 g) as a crude product.

ESIMS m/z: [M+H]⁺ 331.

Step 2

N-([8-{4-(Trifluoromethyl)phenethyl}quinolin-5-yl]methyl)acrylamide(Compound 209)

Compound 209 (0.040 g, 7% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 116-1.

¹H NMR (400 MHz, DMSO-d6, δ): 8.98 (dd, J=4.0, 1.6 Hz, 1H), 8.26 (t,J=5.6 Hz, 1H), 8.52 (dd, J=8.4, 1.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H),7.61-7.56 (m, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.2 Hz, 1H),6.29-6.23 (m, 1H), 6.17-6.12 (m, 1H), 5.62 (dd, J=10.0, 2.4 Hz, 1H),4.79 (d, J=5.6 Hz, 2H), 3.51 (t, J=8.4 Hz, 2H), 3.11 (t, J=8.4 Hz, 2H);

ESIMS m/z: [M+H]⁺ 385.

Example 117

Step 1

5-Bromoquinolin-8-amine (Compound 117-1)

Quinolin-8-amine (0.20 g, 1.38 mmol) was dissolved in acetonitrile (20mL), and N-bromosuccinimide (0.26 g, 1.43 mmol) was added to thesolution. The mixture was stirred at room temperature for 30 minutes.Water was added to the mixture. The organic layer was extracted withethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=90/10→70/30) to obtain compound117-1 (0.15 g, 50%).

¹H NMR (300 MHz, DMSO-d6, δ): 8.76 (d, J=3.3 Hz, 1H), 8.42 (d, J=8.1 Hz,1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 4.2 Hz, 1H), 6.80 (d,J=8.1 Hz, 1H), 5.04 (br, 2H).

Step 2

N-(5-Bromoquinolin-8-yl)-4-(trifluoromethyl)benzamide (Compound 117-2)

Compound 117-1 (0.15 g, 1.20 mmol) was dissolved in DMF (5 mL), andadded to the solution wereO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.38 g, 1.45 mmol), diisopropylethylamine (0.45 mL,2.41 mmol), and 4-(trifluoromethyl)benzoic acid (0.34 g, 1.81 mmol). Themixture was stirred at room temperature for 18 hours. Water was added tothe mixture. The organic layer was extracted with ethyl acetate, driedover anhydrous sodium sulfate, and concentrated under reduced pressureto obtain compound 117-2 (0.15 g, 57%).

¹H NMR (300 MHz, CDCl₃, δ): 10.76 (br, 1H), 8.88 (d, J=3.6 Hz, 1H), 8.82(d, J=8.4 Hz, 1H), 8.58 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 2H), 7.88(d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.64-7.60 (m, 1H).

Step 3

N-(5-Cyanoquinolin-8-yl)-4-(trifluoromethyl)benzamide (Compound 117-3)

Compound 117-3 (0.52 g, 72%) was obtained in the same manner as step 1of example 54, using compound 117-2.

ESIMS m/z: [M+H]⁺ 342.

Step 4

N-{5-(Aminomethyl)quinolin-8-yl}-4-(trifluoromethyl)benzamide (Compound117-4)

Compound 117-4 (0.09 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 117-3.

ESIMS m/z: [M+H]⁺ 346.

Step 5

N-{5-(Acrylamide methyl)quinolin-8-yl}-4-(trifluoromethyl)benzamide(Compound 210)

Compound 210 (0.15 g, 32% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 117-4.

¹H NMR (300 MHz, DMSO-d6, δ): 10.79 (s, 1H), 9.00 (d, J=3.6 Hz, 1H),8.67-8.62 (m, 3H), 8.24 (d, J=8.1 Hz, 2H), 8.00 (d, J=7.8 Hz, 2H),7.76-7.72 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 6.32-6.13 (m, 2H), 5.63 (dd,J=9.6, 2.1 Hz, 1H), 4.82 (d, J=5.4 Hz, 2H);

ESIMS m/z: [M+H]⁺ 400.

Example 118

Step 1

8-[Chloro{4-(trifluoromethyl)phenyl}methyl]quinoline-5-carbonitrile(Compound 118-1)

Compound 113-2 (0.28 g, 0.85 mmol) was dissolved in toluene (5 mL), andthionyl chloride (0.53 g, 4.48 mmol) was added to the solution. Themixture was stirred at room temperature for 3 hours. The toluene in themixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=100/0−>85/15) to obtain compound 118-1 (0.17 g, 57%).

¹H NMR (300 MHz, CDCl₃, δ): 9.05 (d, J=3.9 Hz, 1H), 8.56 (d, J=8.4 Hz,1H), 8.11-8.02 (m, 2H), 7.69-7.64 (m, 4H), 7.57 (d, J=8.1 Hz, 2H).

Step 2

[8-{4-(Trifluoromethyl)benzyl}quinolin-5-yl]methanamine (Compound 118-2)

Compound 118-2 (0.09 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 118-1.

¹H NMR (400 MHz, DMSO-d6, δ): 8.94 (dd, J=4.4, 2.0 Hz, 1H), 8.59 (dd,J=8.4, 1.6 Hz, 1H), 7.63-7.55 (m, 5H), 7.49 (d, J=8.0 Hz, 2H), 4.65 (s,2H), 4.21 (s, 2H).

Step 3

N-([8-{4-(Trifluoromethyl)benzyl}quinolin-5-yl]methyl)acrylamide(Compound 211)

Compound 211 (0.11 g, 6% over two steps) was obtained in the same manneras step 1 of example 76, using compound 118-2.

¹H NMR (400 MHz, DMSO-d6, δ): 8.96 (dd, J=4.0, 1.6 Hz, 1H), 8.62 (br,1H), 8.52 (dd, J=8.4, 1.6 Hz, 1H), 7.65-7.58 (m, 4H), 7.50-7.48 (m, 3H),6.24 (dd, J=17.2, 10.0 Hz, 1H), 6.14 (dd, J=17.2, 2.8 Hz, 1H), 5.61 (dd,J=10.0, 2.8 Hz, 1H), 4.79 (d, J=5.60 Hz, 2H), 4.65 (s, 2H);

ESIMS m/z: [M+H]⁺ 371.

Example 119

Step 1

2-Methyl-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile(Compound 119-1)

Compound 119-1 (0.050 g, 89%) was obtained in the same manner as step 2of example 106, using compound 60-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.45 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.3 Hz,1H), 7.70 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.29-7.24 (m, 2H),7.01 (d, J=8.3 Hz, 1H), 2.83 (s, 3H).

Step 2

[2-Methyl-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methanamine(Compound 119-2)

Compound 119-2 (0.051 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 119-1.

ESIMS m/z: [M+H]⁺ 333.

Step 3

N-([2-Methyl-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 212)

Compound 212 (0.029 g, 49% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 119-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.33 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz,2H), 7.38 (t, J=8.0 Hz, 2H), 7.11 (dd, J=8.0, 2.7 Hz, 3H), 6.37 (dd,J=16.9, 1.3 Hz, 1H), 6.09 (dd, J=16.9, 10.3 Hz, 1H), 5.85 (br, 1H), 5.70(dd, J=10.3, 1.3 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 2.71 (s, 3H);

ESIMS m/z: [M+H]⁺ 387.

Example 120

Step 1

2-Hydroxy-8-{4-(trifluoromethyl)phenoxy}quinoline-5-carbonitrile(Compound 120-1)

Compound 60-2 (0.050 g, 0.14 mmol) was dissolved in DMSO (3 mL), andN-hydroxyacetamide (0.022 g, 0.29 mmol) and potassium carbonate (0.059g, 0.43 mmol) were added to the solution. The mixture was stirred at 80°C. for 2 hours. The mixture was cooled to room temperature, and waterwas added to the mixture. The organic layer was extracted with ethylacetate, washed with saturated saline, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (heptane/ethylacetate=100/0→50/50) to obtain compound 120-1 (0.043 g, 91%).

ESIMS m/z: [M+H]⁺ 331.

Step 2

5-(Aminomethyl)-8-{4-(trifluoromethyl)phenoxy}quinolin-2-ol (Compound120-2)

Compound 120-2 (0.045 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 120-1.

Step 3

N-([2-Hydroxy-8-{4-(trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 213)

Compound 213 (7.0 mg, 13% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 120-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.15 (d, J=9.9 Hz, 1H), 7.65 (d, J=8.5 Hz,2H), 7.16 (dd, J=7.9, 6.1 Hz, 3H), 7.03 (d, J=8.1 Hz, 1H), 6.77 (d,J=9.9 Hz, 1H), 6.35 (dd, J=17.0, 1.3 Hz, 1H), 6.14 (dd, J=17.0, 10.2 Hz,1H), 5.70 (dd, J=10.2, 1.3 Hz, 1H), 4.76 (s, 2H);

ESIMS m/z: [M+H]⁺ 389.

Example 121

Step 1

8-Fluoroquinoline-6-carbonitrile (Compound 121-1)

Compound 121-1 (0.15 g, 83%) was obtained in the same manner as step 1of example 54, using 6-bromo-8-fluoroquinoline.

¹H NMR (400 MHz, CDCl₃, δ): 9.13 (dd, J=4.4, 1.6 Hz, 1H), 8.59-8.54 (m,2H), 8.09 (dd, J=10.4, 1.6 Hz, 1H), 7.82 (dd, J=8.4, 4.0 Hz, 1H).

Step 2

8-{4-(Trifluoromethyl)phenoxy}quinoline-6-carbonitrile (Compound 121-2)

Compound 121-2 (0.16 g, 27%) was obtained in the same manner as step 2of example 50, using compound 121-1.

ESIMS m/z: [M+H]⁺ 315.

Step 3

[8-{4-(Trifluoromethyl)phenoxy}quinolin-6-yl]methanamine (Compound121-3)

Compound 121-3 (0.16 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 121-2.

ESIMS m/z: [M+H]⁺ 319.

Step 4

N-([8-{4-(Trifluoromethyl)phenoxy}quinolin-6-yl methyl]acrylamide(Compound 214)

Compound 214 (0.010 g, 6% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 121-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.18 (dd,J=8.4, 1.6 Hz, 1H), 7.59-7.57 (m, 3H), 7.49-7.46 (m, 1H), 7.19 (d, J=1.6Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.33 (dd, J=16.8, 1.2 Hz, 1H), 6.12(dd, J=16.8, 10.0 Hz, 1H), 5.96 (bs, 1H), 5.72 (dd, J=10.4, 1.6 Hz, 1H),4.66 (d, J=6.0 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 122

Step 1

4-Bromo-8-{4-(trifluoromethyl)phenoxy}quinoline (Compound 122-1)

Compound 122-1 (0.030 g, 37%) was obtained in the same manner as step 1of example 3, using 4-bromoquinolin-8-ol.

ESIMS m/z: [M+H]⁺ 369.

Step 2

8-{4-(Trifluoromethyl)phenoxy}quinoline-4-carbonitrile (Compound 122-2)

Compound 122-2 (0,018 g, 70%) was obtained in the same manner as step 1of example 54, using compound 122-1.

ESIMS m/z: [M+H]⁺ 315.

Step 3

[8-{4-(Trifluoromethyl)phenoxy}quinolin-4-yl]methanamine (Compound122-3)

Compound 122-3 (0.30 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 122-2.

ESIMS m/z: [M+H]⁺ 319.

Step 4

N-([8-{4-(Trifluoromethyl)phenoxy}quinolin-4-yl]methyl)acrylamide(Compound 215)

Compound 215 (0.040 g, 11% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 122-3.

¹H NMR (300 MHz, DMSO-d6, δ): 8.82 (t, J=5.4 Hz 1H), 8.77 (t, J=4.2 Hz,1H), 8.12 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.70-7.61 (m, 3H),7.42 (d, J=4.2 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.39-6.30 (m, 1H),6.21-6.15 (m, 1H), 5.68 (dd, J=9.9, 1.8 Hz, 1H), 4.89 (d, J=5.7 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 123

Step 1

5-Fluoroquinoline-8-carbonitrile (Compound 123-1)

Compound 123-1 (0.15 g, 65%) was obtained in the same manner as step 1of example 54, using 8-bromo-5-fluoroquinoline.

¹H NMR (300 MHz, CDCl₃, δ): 9.17 (dd, J=4.2, 1.5 Hz, 1H), 8.51 (dd,J=8.4, 1.5 Hz, 1H), 8.11 (dd, J=8.1, 5.7 Hz, 1H), 7.63 (dd, J=8.4, 4.2Hz, 1H), 7.31 (t, J=8.7 Hz, 1H).

Step 2

5-{4-(Trifluoromethyl)phenoxy}quinoline-8-carbonitrile (Compound 123-2)

Compound 123-2 (0.10 g, 36%) was obtained in the same manner as step 2of example 50, using compound 123-1.

¹H NMR (400 MHz, DMSO-d6, δ): 9.17 (dd, J=4.0, 1.6 Hz, 1H), 8.69 (dd,J=8.8, 2.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.61(dd, J=8.4, 4.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H).

Step 3

[5-{4-(Trifluoromethyl)phenoxy}quinolin-8-yl]methanamine (Compound123-3)

Compound 123-3 (0.060 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 123-2.

ESIMS m/z: [M+H]⁺ 319.

Step 4

N-([5-{4-(Trifluoromethyl)phenoxy}quinolin-8-yl]methyl)acrylamide(Compound 216)

Compound 216 (0.010 g, 17% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 123-3.

¹H NMR (300 MHz, CDCl₃, δ): 8.97 (dd, J=3.9, 1.5 Hz, 1H), 8.44 (dd,J=8.7, 1.5 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.47(dd, J=8.4, 4.2 Hz, 1H), 7.10-7.01 (m, 4H), 6.28 (dd, J=16.8, 1.2 Hz,1H), 6.09 (dd, J=16.8, 10.2 Hz, 1H), 5.61 (dd, J=9.9, 1.2 Hz, 1H), 5.05(d, J=6.3 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 124

Step 1

8-Bromo-4-chloroquinoline (Compound 124-1)

Phosphorus oxychloride (2.0 mL) was added to 8-bromoquinolin-4-ol (0.10g, 0.44 mmol) at 0° C., and the solution was stirred at 120° C. for 2hours. The mixture was cooled to room temperature and added dropwise toice water (30 mL). The organic layer was extracted with ethyl acetate,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to obtain compound 124-1 (0.070 g, 65%).

¹H NMR (400 MHz, CDCl₃, δ): 8.93 (d, J=4.8 Hz, 1H), 8.25 (dd, J=8.4, 1.2Hz, 1H), 8.13 (dd, J=7.2, 1.2 Hz, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.53-7.49(m, 1H).

Step 2

8-Bromo-4-{4-(trifluoromethyl)phenoxy}quinoline (Compound 124-2)

Compound 124-2 (0.050 g, 33%) was obtained in the same manner as step 2of example 50, using compound 124-1.

¹H NMR (300 MHz, CDCl₃, δ): 8.87 (d, J=5.1 Hz, 1H), 8.31 (d, J=8.4 Hz,1H), 8.13 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.48-7.42 (m, 1H),7.29 (d, J=8.4 Hz, 2H), 6.70 (d, J=5.4 Hz, 1H).

Step 3

4-{4-(Trifluoromethyl)phenoxy}quinoline-8-carbonitrile (Compound 124-3)

Compound 124-3 (0.15 g, 58%) was obtained in the same manner as step 1of example 54, using compound 124-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.91 (d, J=5.2 Hz, 1H), 8.59 (dd, J=8.4, 1.2Hz, 1H), 8.20 (dd, J=7.2, 1.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.69-7.65(m, 1H), 7.32 (d, J=8.4 Hz, 2H), 6.72 (d, J=5.2 Hz, 1H).

Step 4

[4-{4-(Trifluoromethyl)phenoxy}quinolin-8-yl]methanamine (Compound124-4)

Compound 124-4 (0.27 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 124-3.

ESIMS m/z: [M+H]⁺ 319.

Step 5

N-([4-{4-(Trifluoromethyl)phenoxy}quinolin-8-yl]methyl)acrylamide(Compound 217)

Compound 217 (0.050 g, 31% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 124-4.

¹H NMR (300 MHz, CDCl₃, δ): 8.75 (d, J=5.1 Hz, 1H), 8.25 (d, J=8.4 Hz,1H), 7.83 (d, J=6.9 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.56-7.51 (m, 1H),7.30 (dd, J=8.7 Hz, 2H), 7.13 (br, 1H), 6.68 (d, J=5.1 Hz, 1H), 6.27 (d,J=16.5 Hz, 1H), 6.09 (dd, J=17.1, 10.2 Hz, 1H), 5.59 (d, J=10.2 Hz, 1H),5.07 (d, J=6.3 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 125

Step 1

4-{4-(Trifluoromethyl)phenoxy}quinoline-2-carbonitrile (Compound 125-1)

Compound 125-1 (0.30 g, 60%) was obtained in the same manner as step 2of example 50, using 4-chloroquinoline-2-carbonitrile.

¹H NMR (400 MHz, CDCl₃, δ): 8.38 (dd, J=8.4, 0.8 Hz, 1H), 8.18 (d, J=8.8Hz, 1H), 7.92-7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.77-7.73 (m, 1H),7.32 (d, J=8.4 Hz, 2H), 6.85 (s, 1H).

Step 2

[4-{4-(Trifluoromethyl)phenoxy}quinolin-2-yl]methanamine (Compound125-2)

Compound 125-2 (0.12 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 125-1.

ESIMS m/z: [M+H]⁺ 319.

Step 3

N-([4-{4-(Trifluoromethyl)phenoxy}quinolin-2-yl]methyl)acrylamide(Compound 218)

Compound 218 (0.030 g, 13% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 125-2.

¹H NMR (400 MHz, CDCl₃, δ): 8.27 (dd, J=8.4, 0.8 Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.81-7.73 (m, 3H), 7.61-7.57 (m, 1H), 7.28-7.23 (m, 3H), 6.57(s, 1H), 6.36-6.24 (m, 2H), 5.69 (dd, J=9.6, 2.4 Hz, 1H), 4.66 (d, J=4.4Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 126

Step 1

5-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinoline-8-carbonitrile(Compound 126-1)

Compound 126-1 (0.20 g, 54%) was obtained in the same manner as step 2of example 50, using compound 123-1.

ESIMS m/z: [M+H]⁺ 316.

Step 2

(5-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinolin-8-yl)methanamine(Compound 126-2)

Compound 126-2 (0.020 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 126-1.

ESIMS m/z: [M+H]⁺ 320.

Step 3

N-{(5-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]quinolin-8-yl)methyl}acrylamide(Compound 219)

Compound 219 (0.055 g, 20% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 126-2.

¹H NMR (400 MHz, DMSO-d6, δ): 9.00 (dd, J=4.2 Hz, 1H), 8.57 (d, J=2.4Hz, 1H), 8.42 (dd, J=8.4, 1.5 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.63 (d,J=8.4 Hz, 1H), 7.50 (dd, J=8.7, 4.2 Hz, 1H), 7.39-7.30 (m, 1H),7.08-7.01 (m, 2H), 6.28 (dd, J=16.8, 1.5 Hz, 1H), 6.09 (dd, J=17.1, 10.2Hz, 1H), 5.62 (dd, J=10.2, 1.5 Hz, 1H), 5.06 (d, J=6.3 Hz, 2H);

ESIMS m/z: [M+H]⁺ 374.

Example 127

Step 1

5-Bromo-7-fluoroquinoline (Compound 127-1-1) 7-Bromo-5-fluoroquinoline(Compound 127-1-2)

3-Bromo-5-fluoroaniline hydrochloride (4.00 g, 17.66 mmol) and glycerol(3.26 g, 35.50 mmol) were dissolved in nitrobenzene (2 mL). Iron(II)sulfate heptahydrate (0.24 g, 0.06 mmol) and concentrated sulfuric acid(4.8 mL) were added to the solution. The mixture was stirred at 80° C.for 12 hours. The mixture was cooled to room temperature and neutralizedwith a saturated aqueous sodium hydrogen carbonate solution. The organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=95/5−>90/10) to obtain a mixture (2.4 g) of compound 127-1-1 andcompound 127-1-2.

ESIMS m/z: [M+H]⁺ 226.

Step 2

7-Fluoroquinoline-5-carbonitrile (Compound 127-2-1)5-Fluoroquinoline-7-carbonitrile (Compound 127-2-2)

The mixture (0.17 g) of compound 127-2-1 and compound 127-2-2 wasobtained in the same manner as step 2 of example 50, using the mixture(0.27 g, 1.21 mmol) of compound 127-1-1 and compound 127-1-2.

ESIMS m/z: [M+H]³⁰ 173.

Step 3

7-Methoxyquinoline-5-carbonitrile (Compound 127-3-1)5-Methoxyquinoline-7-carbonitrile (Compound 127-3-2)

The mixture (1.2 g, 6.97 mmol) of compound 127-2-1 and compound 127-2-2was dissolved in THF (10 mL), and a 25% methanol solution of sodiummethoxide (0.73 mL, 13.94 mmol) was added to the solution. The mixturewas stirred at 100° C. for 30 minutes. The mixture was left to cool toroom temperature, and water (50 mL) was added to the mixture. Theorganic layer was extracted with dichloromethane, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethylacetate=80/20→70/30) to obtain compound 127-3-1 (0.50 g, 38%) andcompound 127-3-2 (0.40 g, 31%).

Compound 127-3-1: ¹H NMR (300 MHz, CDCl₃, δ): 8.95 (d, J=3.3 Hz, 1H),8.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=6.6 Hz, 2H), 7.49-7.45 (m, 1H), 3.99(s, 3H).

Compound 127-3-2: ¹H NMR (400 MHz, CDCl₃, δ): 9.01 (d, J=2.4 Hz, 1H),8.60 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.54-7.50 (m, 1H), 6.96 (s, 1H),4.05 (s, 3H).

Step 4

(7-Methoxyquinolin-5-yl)methanamine (Compound 127-4)

Compound 127-4 (0.45 g, 88%) was obtained in the same manner as step 2of example 57, using compound 127-3-1.

ESIMS m/z: [M+H]⁺ 189.

Step 5

5-(Aminomethyl)quinolin-7-ol (Compound 127-5)

Pyridine hydrochloride (0.15 g) was added to compound 127-4 (0.45 g,2.39 mmol). The mixture was stirred at 180° C. for one hour using amicrowave reactor. The mixture was left to cool to room temperature. Asaturated aqueous sodium hydrogen carbonate solution (20 mL) was addedto the mixture. The organic layer was extracted with dichloromethane,dried over anhydrous sodium sulfate, concentrated under reduced pressureto obtain compound 127-5 (0.40 g, 54%).

ESIMS m/z: [M+H]⁺ 175.

Step 6

5-(Acrylamidemethyl)quinolin-7-yl acrylate (Compound 127-6)

Compound 127-6 (0.35 g, 54%) was obtained in the same manner as step 1of example 76, using compound 127-5.

¹H NMR (300 MHz, DMSO-d6, δ): 8.84 (dd, J=4.0, 1.2 Hz, 1H), 8.33 (d,J=8.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.26 (d, J=2.4Hz, 1H), 6.60 (dd, J=17.2, 0.8 Hz, 1H), 6.34-6.26 (m, 2H), 6.08-5.99 (m,3H), 5.61 (dd, J=10.4, 1.2 Hz, 1H), 4.88 (d, J=6.0 Hz, 2H).

Step 7

N-{(7-Hydroxyquinolin-5-yl)methyl}acrylamide (Compound 127-7)

Compound 127-6 (0.11 g, 0.38 mmol) was dissolved in methanol (5 mL), andpotassium carbonate (0.10 g, 0.77 mmol) was added to the solution. Themixture was stirred at 80° C. for 30 minutes. The mixture was left tocool to room temperature, and water (20 mL) was added to the mixture.The organic layer was extracted with dichloromethane, dried overanhydrous sodium sulfate, concentrated under reduced pressure to obtaincompound 127-7 (0.20 g, 70%).

¹H NMR (400 MHz, DMSO-d6, δ): 10.15 (s, 1H), 8.75-8.73 (m, 1H),8.67-8.66 (m, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.4, 4.4 Hz, 1H),7.16-7.10 (m, 2H), 6.29 (dd, J=16.8, 10.0 Hz, 1H), 6.15 (dd, J=16.8, 2.0Hz, 1H), 5.64 (dd, J=10.0, 2.4 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H).

Step 8

N-([7-{4-(Trifluoromethyl)phenoxy}quinolin-5-yl]methyl)acrylamide(Compound 220)

Compound 220 (0.023 g, 14%) was obtained in the same manner as step 1 ofexample 3, using compound 127-7.

¹H NMR (400 MHz, CDCl₃, δ): 8.98 (s, 1H), 8.75-8.70 (m, 2H), 7.84 (d,J=7.6 Hz, 2H), 7.66 (bs, 1H), 7.43 (s, 2H), 7.35 (d, J=7.6 Hz, 2H),6.30-6.12 (m, 2H), 5.64 (d, J=9.2 Hz, 1H), 4.87 (d, J=4.0 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 128

Step 1

6-Fluoroquinoline-8-carbonitrile (Compound 128-1)

Compound 128-1 (0.25 g, 82%) was obtained in the same manner as step 2of example 50, using 8-bromo-6-fluoroquinoline.

¹H NMR (300 MHz, CDCl₃, δ): 9.09 (d, J=3.0 Hz, 1H), 8.21 (dd, J=8.1, 1.2Hz, 1H), 7.92 (dd, J=7.8, 2.7 Hz, 1H), 7.72 (dd, J=8.1, 2.7 Hz, 1H),7.58 (dd, J=8.4, 4.2 Hz, 1H).

Step 2

6-Methoxyquinoline-8-carbonitrile (Compound 128-2)

Compound 128-2 (0.75 g, 64%) was obtained in the same manner as step 3of example 127, using compound 128-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.95 (dd, J=4.4, 2.0 Hz, 1H), 8.12 (dd,J=8.4, 1.6 Hz, 1H), 7.79 (d, J=2.8 Hz, 1H), 7.51-7.49 (m, 1H), 7.32 (d,J=2.8 Hz, 1H), 3.97 (s, 3H).

Step 3

(6-Methoxyquinolin-8-yl)methanamine (Compound 128-3)

Compound 128-3 (0.60 g, 90%) was obtained in the same manner as step 2of example 57, using compound 128-2.

¹H NMR (300 MHz, CDCl₃, δ): 8.76 (dd, J=4.0, 1.6 Hz, 1H), 8.04 (dd,J=8.4, 1.6 Hz, 1H), 7.38-7.26 (m, 2H), 6.96 (d, J=2.8 Hz, 1H), 4.37 (s,2H), 3.92 (s, 3H).

Step 4

8-(Aminomethyl)quinolin-6-ol (Compound 128-4)

Compound 128-4 (0.20 g, 78%) was obtained in the same manner as step 5of example 127, using compound 128-3.

ESIMS m/z: [M+H]⁺ 175.

Step 5

8-(Acrylamidemethyl)quinolin-6-yl acrylate (Compound 128-5)

Compound 128-5 (0.11 g, 27%) was obtained in the same manner as step 1of example 76, using compound 128-4.

ESIMS m/z: [M+H]⁺ 283.

Step 6

N-{(6-Hydroxyquinolin-8-yl)methyl}acrylamide (Compound 128-6)

Compound 128-6 (0.070 g, 86%) was obtained in the same manner as step 7of example 127, using compound 128-5.

ESIMS m/z: [M+H]⁺ 229.

Step 7

N-([6-{4-(Trifluoromethyl)phenoxy}quinolin-8-yl]methyl)acrylamide(Compound 221)

Compound 221 (6.0 mg, 4%) was obtained in the same manner as step 1 ofexample 3, using compound 128-6.

¹H NMR (400 MHz, CDCl₃, δ): 8.90 (dd, J=4.4, 1.6 Hz, 1H), 8.11 (dd,J=8.4, 1.6 Hz, 1H), 7.65-7.52 (m, 3H), 7.49-7.46 (m, 1H), 7.31-7.24 (m,2H), 7.14 (d, J=8.4 Hz, 2H), 6.26 (dd, J=16.8, 1.2 Hz, 1H), 6.10 (dd,J=16.8, 10.0 Hz, 1H), 5.61 (d, J=10.4, 1.6 Hz, 1H), 5.05 (d, J=6.0 Hz,2H);

ESIMS m/z: [M+H]⁺ 373.

Example 129

Step 1

4-Bromo-1-{4-(trifluoromethyl)phenoxy}isoquinoline (Compound 129-1)

Compound 129-1 (0.50 g) was obtained as a crude product in the samemanner as step 2 of example 50, using 4-bromo-1-chloroisoquinoline.

ESIMS m/z: [M+H]⁺ 369.

Step 2

1-{4-(Trifluoromethyl)phenoxy}isoquinoline-4-carbonitrile (Compound129-2)

Compound 129-2 (0.20 g, 43% over two steps) was obtained in the samemanner as step 1 of example 54, using compound 129-1.

¹H NMR (300 MHz, DMSO-d6, δ): 8.62 (s, 1H), 8.56 (d, J=8.1 Hz, 1H),8.14-8.09 (m, 2H), 7.98-7.88 (m, 3H), 7.60 (d, J=8.7 Hz, 2H).

Step 3

[1-{4-(Trifluoromethyl)phenoxy}isoquinolin-4-yl]methanamine (Compound129-3)

Compound 129-3 (0.15 g) was obtained as a crude product in the samemanner as step 2 of example 57, using compound 129-2.

ESIMS m/z: [M+H]⁺ 319.

Step 4

N-([1-{4-(Trifluoromethyl)phenoxy}isoquinolin-4-yl]methyl)acrylamide(Compound 222)

Compound 222 (0.070 g, 30% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 129-3.

¹H NMR (400 MHz, DMSO-d6, δ): 8.58 (t, J=5.6 Hz, 1H), 8.42 (d, J=7 Hz,1H), 8.12 (d, J=8.4 Hz, 1H), 7.95-7.91 (m, 2H), 7.84 (d, J=8.4 Hz, 2H),7.78 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 6.25-6.11 (m, 2H), 5.61(dd, J=9.6, 2.8 Hz, 1H), 4.71 (d, J=5.2 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 130

Step 1

8-Fluoroisoquinoline-5-carbonitrile (Compound 130-1)

Compound 130-1 (0.30 g, 87%) was obtained in the same manner as step 1of example 54, using 5-bromo-8-fluoroisoquinoline.

¹H NMR (400 MHz, DMSO-d6, δ): 9.64 (d, J=0.8 Hz, 1H), 8.88 (d, J=6.0 Hz,1H), 8.53 (dd, J=8.0, 5.2 Hz, 1H), 8.03-8.01 (m, 1H), 7.75-7.71 (m, 1H).

Step 2

8-{4-(Trifluoromethyl)phenoxy}isoquinoline-5-carbonitrile (Compound130-2)

Compound 130-2 (0.35 g, 76%) was obtained in the same manner as step 2of example 50, using compound 130-1.

¹H NMR (400 MHz, DMSO-d6, δ): 9.83 (s, 1H), 8.84 (d, J=6.0 Hz, 1H), 8.03(dd, J=6.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.31(d, J=8.8 Hz, 2H), 6.86 (d, J=8.0 Hz, 1H).

Step 3

[8-{4-(Trifluoromethyl)phenoxy}isoquinolin-5-yl]methanamine (Compound130-3)

Compound 130-3 (0.20 g, 66%) was obtained in the same manner as step 2of example 57, using compound 130-2.

ESIMS m/z: [M+H]⁺ 319.

Step 4

N-([8-{4-(Trifluoromethy)phenoxy}isoquinolin-5-yl]methyl)acrylamide(Compound 223)

Compound 223 (0.028 g, 14%) was obtained in the same manner as step 1 ofexample 76, using compound 130-3.

¹H NMR (300 MHz, DMSO-d6, δ): 9.43 (d, J=0.8 Hz, 1H), 8.70-8.65 (m, 2H),8.04 (dd, J=6.0, 1.2 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.0 Hz,1H), 7.27-7.25 (m, 3H), 6.27 (dd, J=16.8, 10.0 Hz, 1H), 6.16 (dd,J=17.2, 2.4 Hz, 1H), 5.64 (dd, J=9.6, 2.0 Hz, 1H), 4.80 (d, J=6.0 Hz,2H);

ESIMS m/z: [M+H]⁺ 373.

Example 131

Step 1

1-Chloro-4-{4-(trifluoromethyl)phenoxy}isoquinoline (Compound 131-1)

Compound 131-1 (0.45 g, 25%) was obtained in the same manner as step 1of example 3, using 1-chloroisoquinolin-4-ol.

ESIMS m/z: [M+H]⁺ 324.

Step 2

4-{4-(Trifluoromethyl)phenoxy}isoquinoline-1-carbonitrile (Compound131-2)

Compound 131-2 (0.32 g, 73%) was obtained in the same manner as step 1of example 54, using compound 131-1.

¹H NMR (300 MHz, DMSO-d6, δ): 8.39 (s, 1H), 8.35-8.25 (m, 2H), 8.05-8.02(m, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H);

ESIMS m/z: [M+H]⁺ 315.

Step 3

[4-{4-(Trifluoromethyl)phenoxy}isoquinolin-1-yl]methanamine (Compound131-3)

Compound 131-2 (0.20 g, 0.63 mmol) was dissolved in ethanol (10 mL), andnickel chloride hexahydrate (0.010 g, 0.063 mmol) and sodium borohydride(0.070 g, 1.90 mmol) were added to the solution. The mixture was stirredat room temperature for 2 hours. The mixture was filtered with Celite®.The filtrate was concentrated under reduced pressure to obtain compound131-3 (0.20 g) as a crude product.

ESIMS m/z: [M+H]⁺ 319.

Step 4

N-([4-{4-(Trifluorophenyl)phenoxy}isoquinolin-1-yl]methyl)acrylamide(Compound 224)

Compound 224 (0.050 g, 22% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 131-3.

¹H NMR (400 MHz, DMSO-d6, δ): 8.75-8.74 (m, 1H), 8.40 (d, J=8.0 Hz, 1H),8.33 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.86-7.77 (m, 2H), 7.74 (d, J=8.8Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.39-6.32 (m, 1H), 6.19-6.14 (m, 1H),5.63 (dd, J=10.0, 2.0 Hz, 1H), 5.03 (d, J=5.6 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 132

Step 1

8-Bromo-5-methoxyisoquinoline (Compound 132-1)

5-Methoxyisoquinoline (0.20 g, 1.25 mmol) was dissolved in acetic acid(5 mL), and bromine (0.20 g, 1.25 mmol) was added to the solution at 0°C. The mixture was stirred at room temperature for 16 hours. Water (50mL) was added to the mixture. The organic layer was extracted with ethylacetate, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=80/20→70/30) to obtain compound132-1 (0.10 g, 33%).

¹H NMR (300 MHz, CDCl₃, δ): 9.53 (5, 1H), 8.61 (d, J=5.7 Hz, 1H), 7.99(d, J=5.7 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.00(s, 3H).

Step 2

5-Methoxyisoquinoline-8-carbonitrile (Compound 132-2)

Compound 132-2 (0.30 g, 77%) was obtained in the same manner as step 1of example 54, using compound 132-1.

¹H NMR (400 MHz, CDCl₃, δ): 9.58 (s, 1H), 8.71 (d, J=6.0 Hz, 1H), 8.05(d, J=5.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.10(s, 3H).

Step 3

{5-Methoxyisoquinolin-8-yl}methanamine (Compound 132-3)

Compound 132-3 (0.17 g, 66%) was obtained in the same manner as step 2of example 57, using compound 132-2.

ESIMS m/z: [M+H]⁺ 189.

Step 4

8-(Aminomethyl)isoquinolin-5-ol hydrobromide (Compound 132-4)

Compound 132-4 (0.20 g, 49%) was obtained in the same manner as step 6of example 27, using compound 132-3.

ESIMS m/z: [M+H]⁺ 175.

Step 5

tert-Butyl([5-{(tert-butoxycarbonyl)oxy}isoquinolin-8-yl]methyl)carbamate(Compound 132-5)

Compound 132-4 (1.0 g, 3.93 mmol) was dissolved in dichloromethane (15mL), and diisopropylethylamine (2.1 mL, 11.7 mmol) and di-tert-butyldicarbonate (6.0 mL, 27.55 mmol) were added to the solution. The mixturewas stirred at room temperature for 16 hours. Water (50 mL) was added tothe mixture. The organic layer was extracted with tert-butyl methylether, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=60/40→50/50) to obtain compound132-5 (0.60 g, 41%).

¹H NMR (400 MHz, DMSO-d6, δ): 9.61 (s, 1H), 8.62 (d, J=6.0 Hz, 1H), 7.69(d, J=5.6 Hz, 1H), 7.64-7.62 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 4.70 (d,J=6.0 Hz, 2H), 1.53 (s, 9H), 1.39 (s, 9H).

Step 6

tert-Butyl {(5-hydroxyisoquinolin-8-yl)methyl}carbamate (Compound 132-6)

Compound 132-5 (0.60 g, 1.60 mmol) was dissolved in methanol (10 mL),and potassium carbonate (0.44 g, 3.20 mmol) was added to the solution.The mixture was stirred at 60° C. for 30 minutes. The mixture was leftto cool to room temperature, and water (20 mL) was added to the mixture.The organic layer was extracted with dichloromethane, dried overanhydrous sodium sulfate, concentrated under reduced pressure to obtaincompound 132-6 (0.50 g, 61%).

¹H NMR (400 MHz, DMSO-d6, δ): 10.50 (bs, 1H), 9.42 (s, 1H), 8.48 (d,J=5.6 Hz, 1H), 7.94 (d, J=5.6 Hz, 1H), 7.45-7.44 (m, 1H), 7.32 (d, J=7.6Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 1.38 (s, 9H).

Step 7

tert-Butyl([5-{4-(trifluoromethyl)phenoxy}isoquinolin-8-yl]methyl)carbamate(Compound 132-7)

Compound 132-7 (0.28 g, 36%) was obtained in the same manner as step 1of example 3, using compound 132-6.

ESIMS m/z: [M+H]⁺ 419.

Step 8

[5-{4-(Trifluoromethyl)phenyloxy}isoquinolin-8-yl]methanaminehydrochloride (Compound 132-8)

Compound 132-7 (0.30 g, 0.71 mmol) was dissolved in dichloromethane (10mL), and a 4 mol/L hydrochloric acid solution in 1,4-dioxane (0.04 mL,1.43 mmol) was added to the solution at 0° C. The mixture was stirredfor 16 hours. The mixture was concentrated under reduced pressure. Thesolid obtained was washed with tert-butyl methyl ether to obtaincompound 132-8 (0.15 g, 59%).

ESIMS m/z: [M+H]⁺ 319.

Step 9

N-([5-{4-(Trifluoromethyl)phenoxy}isoquinolin-8-yl]methyl)acrylamide(Compound 225)

Compound 132-8 (0.10 g, 0.28 mmol) was dissolved in DMF (5 mL), andadded to the solution at 0° C. were diisopropylamine (0.10 mL, 0.56mmmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.12 g, 0.33 mmol), and acrylic acid (0.040 g, 0.56mmol). The mixture was stirred at room temperature for 16 hours. Water(10 mL) was added to the mixture. The organic layer was extracted withdichloromethane, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified using a preparativeHPLC to obtain compound 225 (6.0 mg, 6%).

¹H NMR (400 MHz, CDCl₃, δ): 9.47 (s, 1H), 8.55 (s, 1H), 7.86 (d, J=5.6Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.30 (dd, J=16.8, 1.2 Hz, 1H), 6.05 (d,J=17.2, 10.4 Hz, 1H), 5.91 (bs, 1H), 5.64 (dd, J=10.0, 0.8 Hz, 1H), 5.04(d, J=5.6 Hz, 2H);

ESIMS m/z: [M+H]⁺ 373.

Example 133

Step 1

1,7-Naphthyridin-8-amine (Compound 133-1)

Commercially available pyridine-2,3-diamine (2.0 g, 18.34 mmol) wasdissolved in concentrated sulfuric acid (10 mL) and water (20 mL), andglycerol (6.69 mL, 91.74 mmol) and sodium 3-nitrobenzenesulfonate (8.25g, 36.69 mmol) were added to the solution. The mixture was stirred at135° C. for 36 hours. The mixture was cooled, and a 6 mol/L aqueoussodium hydroxide solution was added to the mixture to bring pH to 10.Thereafter, the organic layer was extracted with ethyl acetate, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(dichloromethane/methanol=100/0→92/8) to obtain compound 133-1 (0.50 g,20%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (dd, J=4.0 Hz, 1.6 Hz, 1H), 8.16 (dd,J=6.8 Hz, 1.6 Hz, 1H), 7.85 (d, J=5.6 Hz, 1H), 7.66 (dd, J=8.4 Hz, 4.4Hz, 1H), 6.94 (s, 2H), 6.91 (d, J=5.6 Hz, 1H).

Step 2

5-Bromo-1,7-naphthyridin-8-amine (Compound 133-2)

Compound 133-1 (0.50 g, 3.44 mmol) was dissolved in acetic acid (5 mL),and bromine (1.18 mL) was added to the solution. The mixture was stirredat 90° C. for 3 hours. The mixture was cooled, and ammonia water wasadded to the mixture to bring pH to 7. Thereafter, the precipitatedsolid was filtered off and dried under reduced pressure to obtaincompound 133-2 (0.45 g, 53%).

¹H NMR (300 MHz, DMSO-d₆, δ): 8.87-8.86 (m, 1H), 8.24 (d, J=8.4 Hz, 1H),8.05 (s, 1H), 7.84 (dd, J=7.8 Hz, 4.2 Hz, 1H), 7.23 (s, 2H).

Step 3

5-Bromo-8-chloro-1,7-naphthyridine (Compound 133-3)

Compound 133-2 (0.45 g, 3.10 mmol) was dissolved in concentratedhydrochloric acid (5 mL) and water (5 mL), and sodium nitrite (1.05 g,15.51 mmol) dissolved in water (5 mL) was added dropwise to the solutionat −10° C. The mixture was stirred at room temperature for one hour. Themixture was cooled, and a saturated aqueous sodium hydrogen carbonatesolution was added to the mixture to bring pH to 8. The organic layerwas extracted with dichloromethane, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=80/20→60/40) toobtain compound 133-3 (0.15 g, 30%).

¹H NMR (400 MHz, DMSO-d₆, δ): 9.24 (dd, J=4.0 Hz, 1.2 Hz, 1H), 8.72 (s,1H), 8.59 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.58 (dd, J=8.8 Hz, 4.4 Hz, 1H).

Step 4

5-Bromo-8-(4-chlorophenoxy)-1,7-naphthyridine (Compound 133-4)

Compound 133-3 (0.50 g, 2.05 mmol) was dissolved in dimethylformamide(10 mL), and 4-chlorophenol (0.31 g, 2.46 mmol) and potassium carbonate(0.56 g, 4.11 mmol) were added to the solution. The mixture was stirredat 100° C. for one hour using a microwave reactor. The mixture wascooled, and water was added to the mixture. The organic layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=90/10→50/50) to obtaincompound 133-4 (0.50 g, 72%).

¹H NMR (400 MHz, DMSO-d₆, δ): 9.15 (dd, J=4.4 Hz, 1.6 Hz, 1H), 8.50 (dd,J=8.4 Hz, 1.6 Hz, 1H), 8.30 (s, 1H), 8.02 (dd, J=8.8 Hz, 4.4 Hz, 1H),7.53 (dd, J=6.8 Hz, 2.0 Hz, 2H), 7.33 (dd, J=6.8 Hz, 2.4 Hz, 2H).

Step 5

tert-Butyl {8-(4-chlorophenoxy)-1,7-naphthyridin-5-yl}carbamate(Compound 133-5)

Compound 133-4 (0.25 g, 0.75 mmol) was dissolved in dimethylacetamide (5mL), and tert-butyl carbamate (0.175 g, 1.501 mmol), sodiumtert-butoxide (0.144 g, 1.501 mmol), and X-phos (0.035 g, 0.075 mmol)were added to the solution. The mixture was purged with nitrogen.Tris(dibenzylideneacetone)dipalladium (0.034 g, 0.037 mmol) was added tothe mixture. The mixture was stirred at 150° C. for one hour using amicrowave reactor. The mixture was cooled, and water was added to themixture. The organic layer was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=90/10→10/90) to obtain compound 133-5 (0.11 g, 40%).

¹H NMR (400 MHz, DMSO-d₆, δ): 9.31 (s, 1H), 9.06 (d, J=2.8 Hz, 1H), 8.40(d, J=7.6 Hz, 1H), 8.01 (s, 1H), 7.88 (dd, J=8.8 Hz, 4.4 Hz, 1H), 7.50(d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 1.47 (s, 9H).

Step 6

8-(4-Chlorophenoxy)-1,7-naphthyridin-5-amine hydrochloride (Compound133-6)

Compound 133-5 (0.110 g, 0.296 mmol) was dissolved in dichloromethane(10 mL), and a 4 mol/L hydrochloric acid solution in 1,4-dioxane (2.0mL) was added to the solution at 0° C. The mixture was stirred at roomtemperature for 4 hours. The mixture was concentrated under reducedpressure, and the crystals obtained were washed with tert-butyl methylether to obtain compound 133-6 (0.05 g, 62%).

ESIMS m/z: [M+H]⁺ 272.

Step 7

N-{8-(4-chlorophenoxy)-1,7-naphthyridin-5-yl}acrylamide (Compound 226)

Compound 226 (15 mg, 25%) was obtained in the same manner as step 5 ofexample 1, using compound 133-6.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.23 (s, 1H), 9.09 (d, J=2.4 Hz, 1H),8.41 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.92 (dd, J=8.4 Hz, 4.0 Hz, 1H),7.52 (d, J=9.2 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 6.62 (dd, J=17.2 Hz,10.8 Hz, 1H), 6.30 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.86-5.84 (m, 1H).

ESIMS m/z: [M+H]⁺ 326.

Example 134

Step 1

8-(4-Chlorophenoxy)-1,7-naphthyridine-5-carbonitrile (Compound 134-1)

Compound 133-4 (0.25 g, 0.75 mmol) was dissolved in dimethylformamide (5mL), and zinc cyanide (0.113 g, 1.12 mmol) was added to the solution.The mixture was purged with nitrogen.Tetrakis(triphenylphosphine)palladium (0.043 g, 0.037 mmol) was added tothe mixture, and the mixture was stirred at 150° C. for one hour using amicrowave reactor. The mixture was cooled, and water was added to themixture. The organic layer was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=90/10→30/70) to obtain compound 134-1 (0.10 g, 47%).

ESIMS m/z: [M+H]⁺ 282.

Step 2

{8-(4-Chlorophenoxy)-1,7-naphthyridin-5-yl}methanamine (Compound 134-2)

Compound 134-1 (0.10 g, 0.35 mmol) was dissolved in ethanol (10 mL), andammonia water (1.0 mL) and Raney nickel (0.050 g) were added to thesolution. The mixture was stirred under hydrogen atmosphere at roomtemperature for 2 hours. The mixture was filtered with Celite®, and thefiltrate was concentrated under reduced pressure to obtain compound134-2 (0.08 g, 79%).

ESIMS m/z: [M+H]⁺ 286.

Step 3

N-[{8-(4-Chlorophenoxy)-1,7-naphthyridin-5-yl}methyl]acrylamide(Compound 227)

Compound 227 (18 mg, 19%) was obtained in the same manner as step 5 ofexample 1, using compound 134-2.

¹H NMR (300 MHz, DMSO-d₆, δ): 9.08-9.07 (m, 1H), 8.62 (t, J=5.1 Hz, 1H),8.56-8.53 (m, 1H), 7.98 (s, 1H), 7.92 (dd, J=8.4 Hz, 4.2 Hz, 1H), 7.52(d, J=8.7 Hz, 2H), 7.27 (d, J=9.0 Hz, 2H), 6.25-6.15 (m, 2H), 5.63-5.94(m, 1H), 4.70 (d, J=5.4 Hz, 2H).

ESIMS m/z: [M+H]⁺ 340.

Example 135

Step 1

6,7-Dihydroisoquinolin-8(5H)-one (Compound 135-1)

Commercially available 5,6,7,8-tetrahydroisoquinoline (1.00 g, 7.51mmol) was dissolved in water (33.4 mL) and acetic acid (0.56 mL), andpotassium permanganate (2.67 g, 16.9 mmol) was added to the solution.The mixture was stirred at room temperature for 30 minutes. The mixturewas filtered with Celite®, and a saturated aqueous sodium bicarbonatesolution was added to the filtrate. The organic layer was extracted withdichloromethane, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (heptane/ethyl acetate=80/20→50/50) to obtaincompound 135-1 (0.17 g, 16%).

¹H NMR (400 MHz, CDCl3, δ): 9.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H), 7.20(dd, J=5.1, 0.7 Hz, 1H), 2.97 (t, J=6.1 Hz, 2H), 2.70 (t, J=6.5 Hz, 2H),2.22-2.15 (m, 2H).

ESIMS m/z: [M+H]⁺ 148.

Step 2

5,6,7,8-Tetrahydroisoquinolin-8-ol (Compound 135-2)

Compound 135-2 (0.17 g, 95%) was obtained in the same manner as step 1of example 15, using compound 135-1 (0.17 g, 1.17 mmol).

¹H NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.01(d, J=5.2 Hz, 1H), 4.87 (t, J=4.5 Hz, 1H), 2.85-2.78 (m, 1H), 2.72-2.68(m, 1H), 2.17 (br, 1H), 2.07-1.90 (m, 3H), 1.85-1.76 (m, 1H).

ESIMS m/z: [M+H]⁺ 150.

Step 3

8-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroisoquinoline (Compound135-3)

Compound 135-3 (0.31 g, 95%) was obtained in the same manner as step 4of example 33, using compound 135-2 (0.17 g, 1.11 mmol) and4-(trifluoromethyl)phenol (0.22 g, 1.33 mmol).

¹H NMR (400 MHz, CDCl3, δ): 8.55 (s, 1H), 8.43 (d, J=4.9 Hz, 1H), 7.59(d, J=8.5 Hz, 2H), 7.10 (d, J=4.9 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 5.49(t, J=3.8 Hz, 1H), 2.91 (dt, J=17.7, 4.6 Hz, 1H), 2.79-2.74 (m, 1H),2.26-2.20 (m, 1H), 2.09-1.98 (m, 2H), 1.87-1.82 (m, 1H).

ESIMS m/z: [M+H]⁺ 294.

Step 4

8-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroisoquinoline-2-oxide(Compound 135-4)

Compound 135-3 (0.31 g, 1.05 mmol) was dissolved in dichloromethane (5.2mL), and m-chloroperoxybenzoic acid (0.62 g, 2.32 mmol) was added to thesolution. The mixture was stirred at room temperature for one hour. Themixture was basified by the addition of a 4 mol/L aqueous sodiumhydroxide solution, and a saturated aqueous sodium thiosulfate solutionwas added to the mixture. The organic layer was extracted withchloroform/methanol, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain compound 135-4 as a crude product.

ESIMS m/z: [M+H]⁺ 310.

Step 5

8-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroisoquinolin-5-ol(Compound 135-5)

Compound 135-4 as a crude product was dissolved in ethyl acetate (10.5mL), and triethylamine (0.44 mL, 3.16 mmol) was added to the solution.Trifluoroacetic acid anhydride (0.30 mL, 2.11 mmol) was added to themixture, and the mixture was stirred at room temperature for 4 hours.The mixture was concentrated under reduced pressure. Ethanol (5.0 mL)and a 2 mol/L aqueous sodium hydroxide solution (2.0 mL) were added tothe residue, and the mixture was stirred at room temperature for onehour. Water was added to the mixture. The organic layer was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was aminosilica gelcolumn chromatography (chloroform/methanol=100/0→90/10→85/15) to obtaincompound 135-5 (145 mg) as a crude product.

ESIMS m/z: [M+H]⁺ 310.

Step 6

8-{4-(Trifluoromethyl)phenoxy}-7,8-tetrahydroisoquinolin-5(6H)-one(Compound 135-6)

Compound 135-5 was dissolved in dichloromethane (4.7 mL), andDess-Martin Periodinane (0.24 mg, 0.57 mmol) was added to the solution.The mixture was stirred at room temperature for 30 minutes. A saturatedaqueous sodium bicarbonate solution was added to the mixture. Theorganic layer was extracted with chloroform, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography(chloroform/methanol=90/10→50/50) to obtain compound 135-6 (0.11 mg, 35%over three steps).

¹H NMR (400 MHz, CDCl3, δ): 8.87 (s, 1H), 8.84 (d, J=5.0 Hz, 1H), 7.85(d, J=5.0 Hz, 1H), 7.63 (d, J=9.1 Hz, 2H), 7.12 (d, J=9.1 Hz, 2H), 5.68(dd, J=5.9, 3.6 Hz, 1H), 3.05 (ddd, J=17.7, 9.3, 5.2 Hz, 1H), 2.73 (ddd,J=17.7, 6.8, 5.2 Hz, 1H), 2.56-2.49 (m, 2H).

ESIMS m/z: [M+H]⁺ 308.

Step 7

8-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroisoquinolin-5-amine(Compound 135-7)

Compound 135-7 was obtained as a crude product in the same manner asstep 2 of example 3, using compound 135-6 (40.0 mg, 0.13 mmol).

ESIMS m/z: [M+H]⁺ 309.

Step 8

N-[8-{4-(Trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroisoquinolin-5-yl]acrylamide(Compound 228)

Compound 228 (1.00 mg, 2% over two steps) was obtained in the samemanner as step 3 of example 17, using compound 135-7.

¹H NMR (400 MHz, CDCl3, δ): 8.59 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 7.60(d, J=8.8 Hz, 2H), 7.30 (d, J=5.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.42(dd, J=16.7, 1.0 Hz, 1H), 6.18 (dd, J=16.7, 10.3 Hz, 1H), 5.85 (d, J=9.0Hz, 1H), 5.79 (dd, J=10.3, 1.0 Hz, 1H), 5.48 (t, J=3.1 Hz, 1H), 5.34(td, J=9.4, 5.4 Hz, 1H), 2.39-2.34 (m, 1H), 2.17-1.99 (m, 3H).

ESIMS m/z: [M+H]⁺ 363.

Example 136N-(8-[{6-(Trifluoromethyl)pyridin-3-yl}oxy]chroman-3-yl)acrylamide(Compounds 229 and 230)

Compound 51 was optically resolved under the following chiralpreparative conditions to obtain compound 229 (137 mg, 45%) having aretention time of 2.61 minutes and compound 230 (135 mg, 44%) having aretention time of 3.28 minutes.

Compound 229: ESIMS m/z: [M+H]⁺ 365.

Compound 230: ESIMS m/z: [M+H]⁺ 365.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IA/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 88% carbon dioxide/12% isopropanol-   Preparative time: 5 minutes-   Flow rate: 30 mL/minute-   Retention time: 2.61 minutes (compound 229), 3.28 minutes (compound    230)

Example 137N-(6-Bromo-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-3-yl)acrylamide(Compounds 231 and 232)

Compound 153 was optically resolved under the following chiralpreparative conditions to obtain compound 231 (7.6 mg, 36%) having aretention time of 2.44 minutes and compound 232 (8.1 mg, 39%) having aretention time of 3.24 minutes.

Compound 231: ESIMS m/z: [M+H]⁺ 443, 445.

Compound 232: ESIMS m/z: [M+H]⁺ 443, 445.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IA/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 86% carbon dioxide/14% methanol-   Preparative time: 5 minutes-   Flow rate: 30 mL/minute-   Retention time: 2.44 minutes (compound 231), 3.24 minutes (compound    232)

Example 138N-[4-Oxo-8-{4-(tolyloromethyl)phenoxy}chroman-3-yl]acrylamide (Compounds233 and 234)

Compound 40 was optically resolved under the following chiralpreparative conditions to obtain compound 233 (24 mg, 48%) having aretention time of 4.56 minutes and compound 234 (22 mg, 44%) having aretention time of 5.07 minutes.

Compound 233: ESIMS m/z: [M+H]⁺ 378.

Compound 234: ESIMS m/z: [M+H]⁺ 378.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® ID/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 88% carbon dioxide/12% methanol-   Preparative time: 10 minutes-   Flow rate: 30 mL/minute-   Retention time: 4.56 minutes (compound 233), 5.07 minutes (compound    234)

Example 139N-(6-Bromo-8-[{6-(trifluoromethyl)pyridin-3-yl}oxy]chroman-3-yl)acrylamide(Compounds 235 and 236)

Compound 153 was optically resolved under the following chiralpreparative conditions to obtain compound 235 (13.5 mg, 45%) having aretention time of 3.67 minutes and compound 236 (12 mg, 40%) having aretention time of 4.35 minutes.

Compound 235: ESIMS m/z: [M+H]⁺ 345.

Compound 236: ESIMS m/z: [M+H]⁺ 345.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IC/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 88% carbon dioxide/12% methanol-   Preparative time: 10 minutes-   Flow rate: 30 mL/minute-   Retention time: 3.67 minutes (compound 235), 4.35 minutes (compound    236)

Example 140N-[8-Methoxy-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compounds 237 and 238)

Compound 33 was optically resolved under the following chiralpreparative conditions to obtain compound 237 having a retention time of5.14 minutes and compound 238 having a retention time of 6.79 minutes.

Compound 237: ESIMS m/z: [M+H]⁺ 394.

Compound 238: ESIMS m/z: [M+H]⁺ 394.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IA/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 95% carbon dioxide/5% methanol→93% carbon    dioxide/7% methanol-   Preparative time: 10 minutes-   Flow rate: 30 mL/minute-   Retention time: 5.14 minutes (compound 237), 6.79 minutes (compound    238)

Example 141N-[8-Fluoro-7-{4-(trifluoromethyl)phenoxy}chroman-4-yl]acrylamide(Compounds 239 and 240)

Compound 31 was optically resolved under the following chiralpreparative conditions to obtain compound 239 having a retention time of6.19 minutes and compound 240 having a retention time of 7.43 minutes.

Compound 239: ESIMS m/z: [M+H]⁺ 382.

Compound 240: ESIMS m/z: [M+H]⁺ 382.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IB/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 96% carbon dioxide/4% methanol-   Preparative time: 10 minutes-   Flow rate: 30 mL/minute-   Retention time: 6.19 minutes (compound 239), 7.43 minutes (compound    240)

Example 142

Step 1

cis-N-[2-Chloro-8-{4-(trifluoromethyl)phenoxy}-5,6,7,8-tetrahydroquinolin-5-yl]acrylamide(Compounds 241 and 242)

Compound 76 was optically resolved under the following chiralpreparative conditions to obtain compound 241 having a retention time of2.73 minutes and compound 242 having a retention time of 3.41 minutes.

Compound 241: ESIMS m/z: [M+H]⁺ 397.

Compound 242: ESIMS m/z: [M+H]⁺ 397.

Chiral Preparative Conditions

-   Apparatus used: SFC30 manufactured by Waters-   Column used: CHIRALPAK® IC/SFC 10 mmϕ×250 mm, 5 μM-   Temperature: 40° C.-   Liquid feeding condition: 88% carbon dioxide/12%    (chloroform:methanol=1:1)-   Preparative time: 4 minutes-   Flow rate: 30 mL/minute-   Retention time: 2.73 minutes (compound 241), 3.41 minutes (Compound    242)

Example 143

Step 1

2-Methylbenzo[d]oxazol-4-ol (Compound 143-1)

2-Aminobenzene-1,3-diol was dissolved in acetonitrile (5 mL), andpentane-2,4-dione (0.24 g, 2.40 mmol), copper(I) iodide (0.030 g, 0.16mmol) and p-toluenesulfonic acid monohydrate (0.030 g, 0.16 mmol) wereadded to the solution. The mixture was stirred at 80° C. for 18 hours ina sealed tube. The mixture was left to cool to room temperature, andwater was added to the mixture. The organic layer was extracted withdichloromethane, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=100/0→80/20) to obtain compound143-1 (0.10 g, 42%).

¹H NMR (400 MHz, CDCl₃, δ): 9.79 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.03(dd, J=8.0, 0.4 Hz, 1H), 6.87 (dd, J=8.0, 0.8 Hz, 1H), 2.69 (s, 3H).

Step 2

4-Methoxy-2-methylbenzo[d]oxazole (Compound 143-2)

Compound 143-1 (0.10 g, 0.67 mmol) was dissolved in DMF (3 mL), andpotassium carbonate (0.18 g, 1.34 mmol) and methyl iodide (0.21 mL, 3.35mmol) were added to the solution. The mixture was stirred at roomtemperature for 18 hours. Water was added to the mixture, the organiclayer was extracted with methyl tert-butyl ether, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtaincompound 143-2 (0.070 g, 64%).

1H NMR (400 MHz, CDCl₃, δ): 7.21 (t, J=8.4 Hz, 1H), 7.09 (dd, J=8.0, 0.4Hz, 1H), 6.77-6.75 (m, 1H), 4.01 (s, 3H), 2.62 (s, 3H).

Step 3

7-Bromo-4-methoxy-2-methylbenzo[d]oxazole (Compound 143-3)

Compound 143-3 (0.060 g, 40%) was obtained in the same manner as step 1of example 117, using compound 143-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.33 (d, J=11.2 Hz, 1H), 6.68 (d, J=11.6Hz, 1H), 4.00 (s, 3H), 2.65 (s, 3H).

Step 4

7-Bromo-2-methylbenzo[d]oxazol-4-ol (Compound 143-4)

Compound 143-4 (0.070 g, 74%) was obtained in the same manner as step 1of example 19, using compound 143-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.48 (s, 1H), 7.31 (d, J=8.8 Hz, 1H),6.69 (d, J=8.8 Hz, 1H), 2.61 (s, 3H).

Step 5

7-Bromo-2-methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound143-5)

Compound 143-5 (0.065 g, 57%) was obtained in the same manner as step 1of example 3, using compound 143-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.59 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.8 Hz,1H), 7.10 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 2.67 (s, 3H).

Step 6

2-Methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile(Compound 143-6)

Compound 143-6 (0.065 g, 57%) was obtained in the same manner as step 1of example 54, using compound 143-5.

¹H NMR (400 MHz, CDCl₃, δ): 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.8 Hz,1H), 7.21 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 2.73 (s, 3H).

Step 7

[2-Methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methanamine(Compound 143-7)

Compound 143-7 was obtained as a crude product in the same manner asstep 3 of example 15, using compound 143-6, and used as it is in thenext reaction.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.70 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.4 Hz,1H), 7.13-7.06 (m, 3H), 3.99 (s, 2H), 2.58 (s, 3H).

Step 8

N-([2-Methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide (Compound 243)

Compound 243 (0.17 g, 65% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 143-7.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.75 (br, 1H), 7.70 (d, J=8.4 Hz, 2H),7.29 (d, J=8.0 Hz, 1H), 7.14-7.08 (m, 3H), 6.30 (dd, J=17.2, 10.4 Hz,1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.65 (dd, J=10.0, 2.0 Hz, 1H), 4.61(d, J=5.6 Hz, 2H), 2.59 (s, 3H);

ESIMS m/z: [M+H]⁺ 377.

Example 144

Step 1

N-(2-Hydroxy-6-methoxyphenyl) propionamide (Compound 144-1)

2-Amino-3-methoxyphenol (3.0 g, 21.58 mmol) was dissolved in toluene (80mL), and propionic anhydride (3.3 mL, 25.90 mmol) was added to thesolution. The mixture was stirred at room temperature for 2 hours. Ethylacetate was added to the mixture, and the organic layer was washed witha saturated sodium bicarbonate aqueous solution and saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=90/10) to obtain compound 144-1 (4.0 g,95%).

¹H NMR (400 MHz, DMSO-d₆, δ): 9.09 (br, 2H), 7.03 (t, J=8.3 Hz, 1H),6.52-6.47 (m, 2H), 3.74 (s, 3H), 2.37 (q, J=7.5 Hz, 2H), 1.11-1.05 (m,3H);

ESIMS m/z: [M+H]⁺ 196.

Step 2

2-Ethyl-4-methoxybenzo[d]oxazole (Compound 144-2)

Compound 144-1 (4.0 g, 20.51 mmol) was dissolved in toluene (70 mL), andp-toluenesulfonic acid (0.388 g, 2.26 mmol) was added to the solution.The mixture was refluxed for 16 hours using a Dean-Stark apparatus.Ethyl acetate was added to the mixture, and the organic layer was washedwith a saturated sodium bicarbonate aqueous solution and saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=95/5) to obtain compound144-2 (2.8 g, 77%).

¹H NMR (400 MHz, DMSO-d₆, δ): 7.29-7.22 (m, 2H), 6.90 (dd, J=7.8, 1.2Hz, 1H), 3.95 (s, 3H), 2.92 (q, J=7.6 Hz, 2H), 1.33 (t, I=7.6 Hz, 3H);

ESIMS m/z: [M+H]⁺ 178.

Step 3

7-Bromo-2-ethyl-4-methoxybenzo[d]oxazole (Compound 144-3)

Compound 144-3 (2.2 g, 55%) was obtained in the same manner as step 1 ofexample 117, using compound 144-2.

¹H NMR (500 MHz, DMSO-d₆, δ): 7.48 (d, J=8.9 Hz, 1H), 6.90 (d, J=8.9 Hz,1H), 3.95 (s, 3H), 2.97 (q, J=7.5 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H);

ESIMS m/z: [M+H]⁺ 256.

Step 4

7-Bromo-2-ethylbenzo[d]oxazol-4-ol (Compound 144-4)

Compound 144-3 (2.22 g, 8.70 mmol) was dissolved in toluene (40 mL), andaluminum chloride (2.32 g, 17.41 mmol) was added to the solution. Themixture was stirred at 80° C. for 1 hour. Water was added to themixture, the organic layer was extracted with ethyl acetate, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toobtain compound 144-4 (1.4 g, 67%). ¹H NMR (500 MHz, CDCl₃, 6): 7.46 (s,1H), 7.31 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.00 (q, J=7.6 Hz,2H), 1.45 (t, J=7.6 Hz, 3H);

ESIMS m/z: [M+H]⁺ 242.

Step 5

7-Bromo-2-ethyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound144-5)

Compound 144-5 (Li g, 49%) was obtained in the same manner as step 1 ofexample 3, using compound 144-4.

¹H NMR (400 MHz, CDCl₃, δ): 7.64-7.58 (m, 2H), 7.39 (d, J=8.6 Hz, 1H),7.14-7.11 (m, 2H), 6.90-6.79 (m, 1H), 3.03-2.94 (m, 2H), 1.51-1.39 (m,3H);

ESIMS m/z: [M+H]⁺ 386.

Step 6

2-Ethyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile(Compound 144-6)

Compound 144-5 (1.0 g, 2.59 mmol) was dissolved in DMF (10 mL), andcopper(I) cyanide (0.450 g, 5.18 mmol) was added to the solution. Themixture was stirred at 120° C. for 2 hours using a micro-wave reactionapparatus. After concentrated under reduced pressure, the mixture waspurified by silica gel column chromatography (petroleum ether/ethylacetate=97/3) to obtain compound 144-6 (0.3 g, 35%).

¹H NMR (400 MHz, CDCl₃, δ): 7.69 (d, J=8.6 Hz, 2H), 7.54-7.50 (m, 1H),7.23 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 1H), 3.07-3.01 (m, 2H),1.50-1.46 (m, 3H);

ESIMS m/z: [M+H]⁺ 333.

Step 7

[2-Ethyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methanamine(Compound 144-7)

Compound 144-7 (0.3 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 144-6, and used as it isin the next reaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.71 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.3 Hz,1H), 7.11-7.07 (m, 3H), 3.99 (br, 2H), 2.94 (q, J=7.6 Hz, 2H), 1.31-1.26(m, 3H);

ESIMS m/z: [M+H]⁺ 337.

Step 8

N-([2-Ethyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide(Compound 244)

Compound 244 (0.080 g, 23% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 144-7.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.72 (t, J=5.5 Hz, 1H), 7.72 (d, J=8.8 Hz,2H), 7.29 (d, J=8.3 Hz, 1H), 7.13-7.09 (m, 3H), 6.34-6.27 (m, 1H),6.17-6.12 (m, 1H), 5.65 (dd, J=10.3, 2.2 Hz, 1H), 4.62 (d, J=5.9 Hz,2H), 2.94 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H);

ESIMS m/z: [M+H]⁺ 391.

Example 145

Step 1

N-(2-Hydroxy-6-methoxyphenyl)isobutylamide (Compound 145-1)

Compound 145-1 (5.4 g) was obtained as a crude product in the samemanner as step 1 of example 144, using 2-amino-3-methoxyphenol andisobutyric anhydride, and used as it is in the next reaction.

¹H NMR (500 MHz, CDCl₃, δ): 10.09 (br, 1H), 7.93 (br, 1H), 7.05-7.02 (m,1H), 6.66-6.61 (m, 1H), 6.47-6.45 (m, 1H), 3.87 (s, 3H), 2.73-2.67 (m,1H), 1.35 (d, J=7.5 Hz, 6H);

ESIMS m/z: [M+H]⁺ 210.

Step 2

2-Isopropyl-4-methoxybenzo[d]oxazole (Compound 145-2)

Compound 145-2 (4.1 g, 74% over two steps) was obtained in the samemanner as step 2 of example 144, using compound 1454.

¹H NMR (500 MHz, CDCl₃, δ): 7.22 (t, J=8.3 Hz, 1H), 7.10 (dd, J=8.5, 1.0Hz, 1H), 6.77-6.75 (m, 1H), 4.01 (s, 3H), 3.26-3.21 (m, 1H), 1.45 (d,J=7.0 Hz, 6H);

ESIMS m/z: [M+H]⁺ 192.

Step 3

7-Bromo-2-isopropyl-4-methoxybenzo[d]oxazole (Compound 145-3)

Compound 145-3 (4.1 g, 71%) was obtained in the same manner as step 1 ofexample 117, using compound 145-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.34 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.8 Hz,1H), 4.00 (s, 3H), 3.31-3.24 (m, 1H), 1.48 (d, J=7.09 Hz, 6H);

ESIMS m/z: [M+H]⁺ 270.

Step 4

7-Bromo-2-isopropylbenzo[d]oxazol-4-ol (Compound 145-4)

Compound 145-4 (3.6 g, 92%) was obtained in the same manner as step 4 ofexample 144, using compound 145-3.

¹H NMR (500 MHz, CDCl₃, δ): 7.30 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 6.75(d, J=8.9 Hz, 1H) 3.31-3.26 (m, 1H), 1.46 (d, J=7.0 Hz, 6H);

ESIMS m/z: [M+H]⁺ 256.

Step 5

7-Bromo-2-isopropyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole(Compound 145-5)

Compound 145-5 (4.0 g, 71%) was obtained in the same manner as step 1 ofexample 3, using compound 145-4.

ESIMS m/z: [M+H]⁺ 400.

Step 6

2-Isopropyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile(Compound 145-6)

Compound 145-6 (0.8 g, 62%) was obtained in the same manner as step 6 ofexample 144, using compound 145-5.

ESIMS m/z: [M+H]⁺ 347.

Step 7

[2-Isopropyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methanamine(Compound 145-7)

Compound 145-7 (0.5 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 145-6, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 351.

Step 8

N-([2-Isopropyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide(Compound 245)

Compound 245 (0.130 g, 24% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 145-7.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.71 (t, J=5.6 Hz, 1H), 7.72 (d, J=8.8 Hz,2H), 7.28 (d, J=8.3 Hz, 1H), 7.15-7.06 (m, 3H), 6.34-6.27 (m, 1H), 6.15(dd, J=17.2, 2.4 Hz, 1H), 5.64 (dd, J=10.0, 2.2 Hz, 1H), 4.63 (d, J=5.9Hz, 2H), 3.29-3.21 (m, 1H), 1.34 (d, J=6.9 Hz, 6H);

ESIMS m/z: [M+H]⁺ 405.

Example 146

Step 1

N-(2-Hydroxy-6-methoxyphenyl)benzamide (Compound 146-1)

Compound 146-1 (7.0 g) was obtained as a crude product in the samemanner as step 1 of example 144, using 2-amino-3-methoxyphenol andbenzoic anhydride, and used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 244.

Step 2

4-Methoxy-2-phenylbenzo[d]oxazole (Compound 146-2)

Compound 146-2 (3.8 g, 78% over two steps) was obtained in the samemanner as step 2 of example 144, using compound 146-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.31-8.29 (m, 2H), 7.53-7.49 (m, 3H),7.31-7.27 (m, 1H), 7.21 (dd, J=8.0, 0.8 Hz, 1H), 6.82 (dd, J=8.1, 0.7Hz, 1H), 4.08 (s, 3H);

ESIMS m/z: [M+H]⁺ 226.

Step 3

7-Bromo-4-methoxy-2-phenylbenzo[d]oxazole (Compound 146-3)

Compound 146-3 (3.5 g, 68%) was obtained in the same manner as step 1 ofexample 117, using compound 146-2.

¹H NMR (500 MHz, CDCl₃, δ): 8.32-8.30 (m, 2H), 7.54-7.50 (m, 3H), 7.39(d, J=8.5 Hz, 1H), 6.73 (d, J=8.9 Hz, 1H), 4.06 (s, 3H);

ESIMS m/z: [M+H]⁺ 304.

Step 4

7-Bromo-4-methoxy-2-phenylbenzo[d]oxazole (Compound 146-4)

Compound 146-4 (3.3 g, quantitatively) was obtained in the same manneras step 4 of example 144, using compound 146-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.24 (d, J=8.1 Hz, 2H), 7.57-7.51 (m, 3H),7.36 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 2.78 (s, 1H);

ESIMS m/z: [M+H]⁺ 290.

Step 5

7-Bromo-2-phenyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound146-5)

Compound 146-5 (3.5 g, 14%) was obtained in the same manner as step 1 ofexample 3, using compound 146-4.

ESIMS m/z: [M+H]⁺ 434.

Step 6

2-Phenyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile(Compound 146-6)

Compound 146-6 (0.7 g, 57%) was obtained in the same manner as step 6 ofexample 144, using compound 146-5.

¹H NMR (500 MHz, CDCl₃, δ): 8.32-8.30 (m, 2H), 7.71 (d, J=8.5 Hz, 2H),7.63-7.49 (m, 5H), 7.29 (d, J=8.5 Hz, 2H);

ESIMS m/z: [M+H]⁺ 381.

Step 7

[2-Phenyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methanamine(Compound 146-7)

Compound 146-7 (0.5 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 146-6, and used as it isin the next reaction.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.19-8.17 (m, 2H), 7.75-7.68 (m, 2H),7.64-7.57 (m, 4H), 7.51-7.45 (m, 2H), 7.19-7.11 (m, 3H), 4.09 (s, 2H).

Step 8

N-([2-Phenyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide (Compound 246)

Compound 246 (0.115 g, 20% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 146-7.

¹H NMR (400 MHz, CD₃OD, δ): 8.24-8.22 (m, 2H), 7.66 (d, J=8.3 Hz, 2H),7.62-7.53 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 7.18 (d, I=8.8 Hz, 2H), 7.05(d, J=8.3 Hz, 1H), 6.33-6.31 (m, 2H), 5.73-5.70 (m, 1H), 4.83 (s, 2H);

ESIMS m/z: [M+H]⁺ 439.

Example 147

Step 1

Benzo[d]oxazol-4-ol (Compound 147-1)

Ortho-methyl formate (5.24 mL, 48 mmol) was added to2-aminobenzene-1,3-diol (4.0 g, 32.0 mmol), and the mixture was stirredat 130° C. for 2 hours. After concentrated under reduced pressure, themixture was purified by silica gel column chromatography (petroleumether/ethyl acetate=76/24) to obtain compound 147-1 (3.5 g, 81%).

¹H NMR (400 MHz, DMSO-d₆, δ): 10.33 (s, 1H), 8.56 (s, 1H), 7.23-7.14 (m,2H), 6.77 (d, J=8.1 Hz, 1H);

ESIMS m/z: [M+H]⁺ 136.

Step 2

4-Methoxybenzo[d]oxazole (Compound 147-2)

Compound 147-1 (3.5 g, 25.92 mmol) was dissolved in acetonitrile (70mL). Methyl iodide (1.64 mL, 25.92 mmol) and potassium carbonate (10.73g, 77.78 mmol) were added to the solution, and the mixture was stirredat 80° C. for 16 hours. Water was added to the mixture and the organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=90/10) to obtain compound 147-2 (2.8 g, 72%).

¹H NMR (500 MHz, DMSO-d₆, δ): 8.62 (s, 1H), 7.38-7.32 (m, 2H), 6.95 (dd,J=7.8, 1.1 Hz, 1H), 3.98 (s, 3H);

ESIMS m/z: [M+H]⁺ 150.

Step 3

7-Bromo-4-methoxybenzo[d]oxazole (Compound 147-3)

Compound 147-3 (1.5 g, 35%) was obtained in the same manner as step 1 ofexample 117, using compound 147-2.

¹H NMR (500 MHz, CDCl₃, δ): 8.06 (s, 1H), 7.45 (d, J=8.9 Hz, 1H), 6.75(d, J=8.5 Hz, 1H), 4.05 (s, 3H);

ESIMS m/z: [M+H]⁺ 228.

Step 4

7-Bromobenzo[d]oxazol-4-ol (Compound 147-4)

Compound 147-4 (1.0 g, 71%) was obtained in the same manner as step 4 ofexample 144, using compound 147-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.66 (s, 1H), 8.68 (s, 1H), 7.42 (d,J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H);

ESIMS m/z: [M+H]⁺ 214.

Step 5

7-Bromo-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound 147-5)

Compound 147-5 (0.3 g, 18%) was obtained in the same manner as step 1 ofexample 3, using compound 147-4.

¹H NMR (400 MHz, CDCl₃, δ): 8.11 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.52(d, J=8.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H);

ESIMS m/z: [M+H]⁺ 358.

Step 6

4-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile (Compound147-6)

Compound 147-6 (0.2 g, 78%) was obtained in the same manner as step 6 ofexample 144, using compound 147-5.

¹H NMR (400 MHz, CDCl₃, δ): 8.19 (s, 1H), 7.68 (dd, J=15.9, 8.6 Hz, 3H),7.24 (d, J=7.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 1H).

Step 7

[4-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methanamine (Compound147-7)

Compound 147-6 (0.200 g, 0.65 mmol) was dissolved in methanol (5 mL),and nickel(II) chloride hexahydrate (0.015 g, 0.06 mmol) was added tothe solution under ice cooling. The mixture was stirred at 0° C. for 10minutes. Sodium borohydride (0.174 g, 4.60 mmol) was added to themixture. The mixture was further stirred at room temperature for 1 hour.The mixture was concentrated under reduced pressure to obtain compound147-7 (0.200 g) as a crude product, which was used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 309.

Step 8

N-([4-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide(Compound 247)

Compound 247 (0.015 g, 6% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 147-7.

¹H NMR (500 MHz, CDCl₃, δ): 8.77 (s, 1H), 8.74 (t, J=5.5 Hz, 1H), 7.72(d, J=8.5 Hz, 2H), 7.39 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.14(d, J=8.5 Hz, 2H), 6.32-6.27 (m, 1H), 6.15 (dd, J=17.1, 2.1 Hz, 1H),5.65 (dd, J=10.4, 2.1 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H);

ESIMS m/z: [M+H]⁺ 363.

Example 148

Step 1

2,2,2-Trifluoro-N-(2-hydroxy-6-methoxyphenyl)acetamide (Compound 148-1)

Compound 1484 (7.0 g) was obtained as a crude product in the same manneras step 1 of example 144, using 2-amino-3-methoxyphenol and anhydroustrifluoroacetic acid, and used as it is in the next reaction.

¹H NMR (400 MHz, CDCl₃, δ): 8.71 (br, 1H), 7.17 (t, J=8.4 Hz, 1H), 6.70(d, J=8.6 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 1H);

ESIMS m/z: [M+H]⁺ 236.

Step 2

4-Methoxy-2-(trifluoromethyl)benzo[d]oxazole (Compound 148-2)

Compound 148-2 (4.0 g, 51% over two steps) was obtained in the samemanner as step 2 of example 144, using compound 148-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.46 (t, J=8.3 Hz, 1H), 7.24 (s, 1H), 6.90(d, J=8.3 Hz, 1H), 4.07 (s, 3H);

ESIMS m/z: [M+H]⁺ 218.

Step 3

7-Bromo-4-methoxy-2-(trifluoromethyl)benzo[d]oxazole (Compound 148-3)

Compound 148-3 (3.5 g, 64%) was obtained in the same manner as step 1 ofexample 117, using compound 148-2.

¹H NMR (500 MHz, CDCl₃, δ): 7.58 (d, J=8.9 Hz, 1H), 6.83 (d, J=8.9 Hz,1H), 4.07 (s, 3H);

ESIMS m/z: [M+H]⁺ 296.

Step 4

7-Bromo-2-(trifluoromethyl)benzo[d]oxazol-4-ol (Compound 148-4)

Compound 148-4 (2.3 g, 69%) was obtained in the same manner as step 4 ofexample 144, using compound 148-3.

¹H NMR (400 MHz, CDCl₃, δ): 7.54 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz,1H), 6.58 (br, 1H);

ESIMS m/z: [M+H]⁺ 282.

Step 5

7-Bromo-2-(trifluoromethyl)-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole(Compound 148-5)

Compound 148-5 (1.05 g, 30%) was obtained in the same manner as step 1of example 3, using compound 148-4.

ESIMS m/z: [M+H]⁺ 426.

Step 6

2-(Trifluoromethyl)-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile(Compound 148-6)

Compound 148-6 (0.200 g, 30%) was obtained in the same manner as step 6of example 144, using compound 148-5.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.19 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.8 Hz,2H), 7.43 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.8 Hz, 1H).

Step 7

N-([2-(Trifluoromethyl)-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide(Compound 248)

Compound 148-6 (0.20 g, 0.54 mmol) was dissolved in THF (6 mL), andtriethylamine (0.14 mL, 1.07 mmol) and Raney nickel (200 mg) were addedto the solution. The mixture was stirred under hydrogen atmosphere atroom temperature for 1 hour.

After completion of the reaction, the reaction vessel was substitutedwith Ar, THF (2 mL) solution of acryloyl chloride (0.034 mL, 0.43 mmol)was added to the mixture under ice cooling, and the mixture was stirredat 0° C. for 1 hour. Ethyl acetate was added to the mixture, and theorganic layer was washed with a saturated sodium bicarbonate aqueoussolution and saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified using apreparative HPLC (ammonium bicarbonate aqueous solution) to obtaincompound 284 (0.040 g, 17%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.80 (t, J=5.7 Hz, 1H), 7.76 (d, J=8.9 Hz,2H), 7.56 (d, J=8.2 Hz, 1H), 7.30-7.23 (m, 3H), 6.32-6.27 (m, 1H),6.17-6.13 (m, 1H), 5.66 (dd, J=10.4, 2.1 Hz, 1H), 4.67 (d, J=5.5 Hz,2H);

ESIMS m/z: [M+H]⁺ 431.

Example 149

Step 1

7-Bromo-2-methyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazole(Compound 149-1)

Compound 143-4 (1.0 g, 4.38 mmol) was dissolved in DMF (5 mL), andcesium carbonate (2.86 g, 8.77 mmol) and5-bromo-2-(trifluoromethyl)pyridine (1.98 g, 8.77 mmol) were added tothe solution. The mixture was stirred at 140° C. for 1.5 hours using amicro-wave reaction apparatus. The mixture was left to cool to roomtemperature, and water and ethyl acetate were added to the mixture. Themixture was filtered with Celite®. The filtrate was extracted with ethylacetate, washed with water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (petroleum ether/ethyl acetate=90/10) toobtain compound 149-1 (0.45 g, 27%).

¹H NMR (400 MHz, CDCl₃, δ): 8.51 (d, J=2.7 Hz, 1H), 7.64 (d, J=8.6 Hz,1H), 7.46 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.6, 2.4 Hz, 1H), 6.93 (d,J=8.4 Hz, 1H), 2.67 (s, 3H);

ESIMS m/z: [M+H]⁺ 373.

Step 2

2-Methyl-4-[{6-(trifloromethyl)pyridin-3-yl}oxy]benzo[d]oxazole-7-carbonitrile(Compound 149-2)

Compound 149-2 (0.14 g, 36%) was obtained in the same manner as step 6of example 144, using compound 149-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.56 (d, J=2.7 Hz, 1H), 7.73 (d, J=8.6 Hz,1H), 7.61 (d, J=8.6 Hz, 1H), 7.53 (dd, J=8.6, 2.9 Hz, 1H), 6.98 (d,J=8.6 Hz, 1H), 2.71 (s, 3H);

ESIMS m/z: [M+H]⁺ 320.

Step 3

N-{(2-Methyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 249)

Compound 249 (0.080 g, 24% over two steps) was obtained in the samemanner as step 7 of example 148, using compound 149-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.74-8.71 (m, 1H), 8.56 (d, J=2.9 Hz, 1H),7.86 (d, J=8.8 Hz, 1H), 7.48 (dd, J=8.8, 2.5 Hz, 1H), 7.31 (d, J=8.3 Hz,1H), 7.22-7.20 (m, 1H), 6.34-6.27 (m, 1H), 6.15 (dd, J=17.2, 2.4 Hz,1H), 5.65 (dd, J=10.3, 2.0 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 2.6 (s, 3H);

ESIMS m/z: [M+H]⁺ 378.

Example 150

Step 1

7-Bromo-2-methyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazole (Compound 150-1)

Compound 143-4 (0.95 g, 4.16 mmol) was dissolved in DMF (15 mL), andcesium carbonate (2.72 g, 8.33 mmol) and

2-chloro-5-(trifluoromethyl)pyridine (1.51 g, 8.33 mmol) were added tothe solution. The mixture was stirred at 100° C. for 2 hours. Themixture was left to cool to room temperature, and water and ethylacetate were added to the mixture. The mixture was filtered withCelite®. The filtrate was extracted with ethyl acetate, washed withwater, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=90/10) to obtain compound150-1 (1.1 g, 71%).

¹H NMR (500 MHz, CDCl₃, δ): 8.364-8.360 (m, 1H), 7.96-7.94 (m, 1H), 7.48(d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 2.64(s, 3H); ESIMS m/z: [M+H]⁺ 373.

Step 2

2-Methyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazole-7-carbonitrile(Compound 150-2)

Compound 150-2 (0.26 g, 28%) was obtained in the same manner as step 6of example 144, using compound 150-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (s, 1H), 8.00 (dd, J=8.8, 2.5 Hz, 1H),7.65 (d, J=8.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 2H), 2.67 (s, 3H);

ESIMS m/z: [M+H]⁺ 320.

Step 3

N-{(2-Methyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 250)

Compound 250 (0.080 g, 32% over two steps) was obtained in the samemanner as step 7 of example 148, using compound 150-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.8 (m, 1H), 8.5 (s, 1H), 8.26 (dd, J=8.8,2.5 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.19 (d,J=8.4 Hz, 1H), 6.34-6.27 (m, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.64(dd, J=10.0, 2.2 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.57 (s, 3H);

ESIMS m/z: [M+H]⁺ 378.

Example 151

Step 1

7-Bromo-2-ethyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazole(Compound 151-1)

Compound 151-1 (0.65 g, 41%) was obtained in the same manner as step 1of example 150, using compound 144-4 and5-bromo-2-(trifluoromethyl)pyridine.

ESIMS m/z: [M+H]⁺ 387.

Step 2

2-Ethyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazole-7-carbonitrile(Compound 151-2)

Compound 151-2 (0.20 g, 39%) was obtained in the same manner as step 6of example 144, using compound 151-1.

ESIMS m/z: [M+H]⁺ 334.

Step 3

N-{(2-Ethyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 251)

Compound 251 (0.040 g, 14% over two steps) was obtained in the samemanner as step 7 of example 148, using compound 151-2.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.73 (t, J=5.5 Hz, 1H), 8.59 (d, J=3.1 Hz,1H), 7.87 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.5, 2.8 Hz, 1H), 7.31 (d,J=8.2 Hz, 1H), 7.19-7.16 (m, 1H), 6.33-6.28 (m, 1H), 6.15 (dd, J=17.1,2.1 Hz, 1H), 5.65 (dd, J=10.2, 2.0 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 2.94(q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H);

ESIMS m/z: [M+H]⁺ 392.

Example 152

Step 1

7-Bromo-2-ethyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazole(Compound 152-1)

Compound 152-1 (3.0 g, 63%) was obtained in the same manner as step 1 ofexample 150, using compound 144-4 and2-chloro-5-(trifluoromethyl)pyridine.

¹H NMR (500 MHz, CDCl₃, δ): 8.367-8.365 (m, 1H), 7.96-7.93 (m, 1H), 7.47(d, J=8.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.96(q, J=7.6 Hz, 2H), 1.41 (t, J=7.6 Hz, 3H);

ESIMS m/z: [M+H]⁺ 387.

Step 2

2-Ethyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazole-7-carbonitrile(Compound 152-2)

Compound 152-2 (0.55 g, 43%) was obtained in the same manner as step 6of example 144, using compound 152-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.379-8.374 (m, 1H), 8.01 (dd, J=8.75, 2.25Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.26-7.23 (m, 2H), 2.99 (q, J=7.5 Hz,2H), 1.42 (t, J=7.5 Hz, 3H);

ESIMS m/z: [M+H]⁺ 334.

Step 3

N-{(2-Ethyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 252)

Compound 252 (0.11 g, 17% over two steps) was obtained in the samemanner as step 7 of example 148, using compound 152-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=5.6 Hz, 1H), 8.50 (d, J=1.0 Hz,1H), 8.26 (dd, J=8.8, 2.5 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.28 (d,J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.34-6.27 (m, 1H), 6.15 (dd,J=17.6, 2.0 Hz, 1H), 5.64 (dd, J=10.2, 2.0 Hz, 1H), 4.61 (d, J=5.4 Hz,2H), 2.91 (q, J=7.34 Hz, 2H), 1.27 (t, J=7.4 Hz, 3H);

ESIMS m/z: [M+H]⁺ 392.

Example 153

Step 1

2-Methylbenzo[d]oxazol-7-ol (Compound 153-1)

Compound 153-1 (1.4 g) was obtained as a crude product in the samemanner as step 1 of example 147, using 3-aminobenzene-1,2-diol, and usedas it is in the next reaction.

¹H NMR (400 MHz, CDCl₃, δ): 7.24 (d, J=8.1 Hz, 1H), 7.16 (t, J=8.0 Hz,1H), 6.83 (d, J=7.8 Hz, 1H), 5.67 (br, 1H), 2.65 (s, 3H);

ESIMS m/z: [M+H]⁺ 150.

Step 2

7-Methoxy-2-methylbenzo[d]oxazole (Compound 153-2)

Compound 153-2 (1.0 g, 77% over two steps) was obtained in the samemanner as step 2 of example 147, using compound 153-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.27 (br, 1H), 7.24-7.20 (m, 1H), 6.83 (dd,J=7.8, 1.2 Hz, 1H), 4.02 (s, 3H), 2.65 (s, 3H);

ESIMS m/z: [M+H]⁺ 164.

Step 3

4-Bromo-7-methoxy-2-methylbenzo[d]oxazole (Compound 153-3)

Compound 153-3 (1.2 g, 81%) was obtained in the same manner as step 1 ofexample 117, using compound 153-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.38 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.6 Hz,1H), 4.00 (s, 3H), 2.68 (s, 3H);

ESIMS m/z: [M+H]⁺ 242.

Step 4

4-Bromo-2-methylbenzo[d]oxazol-7-ol (Compound 153-4)

Compound 153-4 (1.0 g, 88%) was obtained in the same manner as step 4 ofexample 144, using compound 153-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.77 (s, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.79(d, J=8.8 Hz, 1H), 2.71 (s, 3H);

ESIMS m/z: [M+H]⁺ 228.

Step 5

4-Bromo-2-methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound153-5)

Compound 153-5 (1.0 g, 61%) was obtained in the same manner as step 1 ofexample 3, using compound 153-4.

¹H NMR (400 MHz, CDCl₃, δ): 7.61 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.6 Hz,1H), 7.08 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.6 Hz, 1H), 2.66 (s, 3H);

ESIMS m/z: [M+H]⁺ 372.

Step 6

2-Methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole-4-carbonitrile(Compound 153-6)

Compound 153-6 (0.5 g) was obtained as a crude product in the samemanner as step 6 of example 144, using compound 153-5, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 319.

Step 7

[2-Methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-4-yl]methanamine(Compound 153-7)

Compound 153-7 (0.5 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 153-6, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 323.

Step 8

N-([2-Methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]oxazol-4-yl]methyl)acrylamide(Compound 253)

Compound 253 (0.080 g, 8% over three steps) was obtained in the samemanner as step 5 of example 1, using compound 153-7.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.69 (t, J=5.7 Hz, 1H), 7.74 (d, J=8.5 Hz,2H), 7.26 (d, J=8.2 Hz, 1H), 7.16 (dd, J=8.4, 2.6 Hz, 3H), 6.34-6.29 (m,1H), 6.14 (dd, J=17.1, 2.1 Hz, 1H), 5.63 (dd, J=10.5, 2.5 Hz, 1H), 4.65(d, J=5.8 Hz, 2H), 2.61 (s, 3H);

ESIMS m/z: [M+H]⁺ 377.

Example 154

Step 1

2-(Chloromethyl)benzo[d]oxazol-4-ol (Compound 154-1)

2-Aminobenzene-1,3-diol (0.50 g, 4.00 mmol) was dissolved in the mixedsolvent of dichloromethane (5 mL) and THF (5 mL), and ethyl2-chloroacetimidate hydrochloride (0.74 g, 4.00 mmol) was added to thesolution under ice cooling. The mixture was stirred at room temperaturefor 16 hours. Water was added to the mixture, and the organic layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain compound 154-1 (0.40 g,54%).

¹H NMR (400 MHz, CDCl₃, δ): 8.16 (s, 1H), 7.30 (t, J=16.4 Hz, 1H), 7.12(dd, J=8.4, 0.8 Hz, 1H), 6.91 (dd, J=8.4, 0.8 Hz, 1H), 4.82 (s, 2H),

Step 2

2-(Chloromethyl)-4-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound154-2)

Compound 154-2 (0.060 g, 34%) was obtained in the same manner as step 1of example 3, using compound 154-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.61 (d, J=8.4 Hz, 2H), 7.38 (m, 2H), 7.14(d, J=8.4 Hz, 2H), 6.95 (dd, J=7.6, 1.2 Hz, 1H), 4.74 (s, 2H).

Step 3

2-([4-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-2-yl]methyl)isoindoline-1,3-diol(Compound 154-3)

Compound 154-2 (0.30 g, 0.91 mmol) was dissolved in DMF (5 mL), andpotassium carbonate (0.37 g, 2.75 mmol) and phthalimide potassium salt(0.20 g, 1.10 mmol) were added to the solution. The mixture was stirredat 100° C. for 30 minutes using a micro-wave reaction apparatus. Themixture was left to cool to room temperature and water was added to themixture. The organic layer was extracted with ethyl acetate, washed withwater, dried over anhydrous sodium sulfate, and concentrated underreduced pressure.

The residue was purified by silica gel column chromatography(hexane/ethyl acetate=70/30→50/50) to obtain compound 154-3 (0.40 g,91%).

¹H NMR (300 MHz, DMSO-d₆, δ): 7.95-7.91 (m, 4H), 7.69 (d, J=8.4 Hz, 2H),7.62 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H),7.08 (d, J=8.1 Hz, 1H), 5.13 (s, 2H).

Step 4

[4-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-2-yl]methanamine (Compound154-4)

Compound 154-3 (0.40 g, 0.91 mmol) was dissolved in methanol (10 mL),and hydrazine monohydrate (0.040 g, 0.91 mmol) was added to thesolution. The mixture was stirred at room temperature for 30 minutes.After concentrated under reduced pressure, the mixture was purified bysilica gel column chromatography (hexane/ethyl acetate=50/50→30/70) toobtain compound 154-4 (0.25 g, 89%).

ESIMS m/z: [M+H]⁺ 309.

Step 5

N-([4-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-2-yl]methyl)acrylamide(Compound 254)

Compound 254 (0.045 g, 19%) was obtained in the same manner as step 1 ofexample 76, using compound 154-4.

¹H NMR (300 MHz, DMSO-d₆, δ): 8.91 (br, 1H), 7.72 (d, J=8.7 Hz, 2H),7.65 (d, J=7.8 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.16-7.13 (m, 3H), 6.29(dd, J=17.4, 10.2 Hz, 1H), 6.13 (d, J=17.7 Hz, 1H), 5.66 (d, J=9.3 Hz,1H), 4.63 (d, J=6.0 Hz, 2H);

ESIMS m/z: [M+H]⁺ 363.

Example 155

Step 1

2-(Chloromethyl)benzo[d]oxazol-5-ol (Compound 155-1)

Compound 155-1 (0.11 g, 93%) was obtained in the same manner as step 1of example 154, using 2-aminobenzene-1,4-diol.

¹H NMR (300 MHz, CDCl₃, δ): 7.40 (d, J=8.7 Hz, 1H), 7.17 (d, J=2.4 Hz,1H), 6.92 (dd, J=8.7, 2.4 Hz, 1H), 5.24 (s, 1H), 4.72 (s, 2H).

Step 2

2-(Chloromethyl)-5-{4-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound155-2)

Compound 155-2 (0.050 g, 35%) was obtained in the same manner as step 1of example 3, using compound 155-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.58-7.55 (m, 3H), 7.42 (d, J=2.4 Hz, 1H),7.13 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.76 (s, 2H).

Step 3

2-([5-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-2-yl]methyl)isoindoline-1,3-diol(Compound 155-3)

Compound 155-3 (0.80 g, 51%) was obtained in the same manner as step 3of example 154, using compound 155-2.

ESIMS m/z: [M+H]⁺ 439.

Step 4

[5-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-2-yl]methanamine (Compound155-4)

Compound 155-4 (0.50 g, 89%) was obtained in the same manner as step 4of example 154, using compound 155-3.

ESIMS m/z: [M+H]⁺ 309.

Step 5

N-([5-{4-(Trifluoromethyl)phenoxy}benzo[d]oxazol-2-yl]methyl)acrylamide(Compound 255)

Compound 255 (0.10 g, 21%) was obtained in the same manner as step 1 ofexample 76, using compound 155-4.

¹H NMR (400 MHz, CDCl₃, δ): 7.58-7.51 (m, 3H), 7.37 (d, J=2.4 Hz, 1H),7.08 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.42-6.38 (m, 2H),6.23 (dd, J=17.2, 10.4 Hz, 1H), 5.76 (dd, J=10.4, 1.2 Hz, 1H), 4.83 (d,J=5.2 Hz, 2H);

ESIMS m/z: [M+H]⁺ 363.

Example 156

Step 1

N-(2-Methoxyphenyl)ethanethioamide (Compound 156-1)

N-(2-Methoxyphenyl)acetamide (10.0 g, 60.60 mmol) was dissolved inchlorobenzene (40 mL), and2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide(12.24 g, 30.30 mmol) was added to the solution. The mixture was stirredat 120° C. for 4 hours. The mixture was left to cool to roomtemperature, and was purified by silica gel column chromatography(hexane/ethyl acetate=100/0→90/10) to obtain compound 156-1 (8.0 g,72%).

¹H NMR (500 MHz, CDCl₃, δ): 9.12 (br, 1H), 7.21-7.17 (m, 1H), 7.03-6.93(m, 3H), 3.91 (s, 3H), 2.77 (s, 3H).

Step 2

4-Methoxy-2-methylbenzo[d]thiazole (Compound 156-2)

Compound 156-1 (8.0 g, 44.19 mmol) was dissolved in water (480 mL).Potassium hydroxide (11.38 g, 203.27 mmol) and potassium ferricyanide(33.40 g, 101.65 mmol) were added to the solution, and the mixture wasstirred at 100° C. for 4 hours. The mixture was left to cool to roomtemperature and water was added to the mixture. The organic layer wasextracted with ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=100/0→80/20) to obtaincompound 156-2 (2.0 g, 25%).

¹H NMR (400 MHz, CDCl₃, δ): 7.40 (dd, J=8.0, 0.8 Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 6.88 (dd, J=8.0, 0.4 Hz, 1H), 4.03 (s, 3H), 2.84 (s, 3H).

Step 3

7-Bromo-4-methoxy-2-methylbenzo[d]thiazole (Compound 156-3)

Compound 156-3 (1.20 g, 42%) was obtained in the same manner as step 1of example 117, using compound 156-2.

¹H NMR (400 MHz, CDCl₃, δ): 7.40 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.4 Hz,1H), 4.02 (s, 3H), 2.84 (s, 3H).

Step 4

7-Bromo-2-methylbenzo[d]thiazol-4-ol (Compound 156-4)

Compound 156-4 (0.065 g, 69%) was obtained in the same manner as step 1of example 19, using compound 156-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.42 (s, 1H), 7.39 (d, J=8.4 Hz, 1H),6.82 (d, J=8.4 Hz, 1H), 2.79 (s, 3H).

Step 5

7-Bromo-2-methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]thiazole(Compound 156-5)

Compound 156-5 (0.050 g, 49%) was obtained in the same manner as step 1of example 3, using compound 156-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.60 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz,1H), 7.13 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.8 Hz, 1H), 2.84 (s, 3H).

Step 6

2-Methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]thiazole-7-carbonitrile(Compound 156-6)

Compound 156-6 (0.220 g, 46%) was obtained in the same manner as step 1of example 54, using compound 156-5.

¹H NMR (400 MHz, CDCl₃, δ): 7.69 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.4 Hz,1H), 7.25 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 2.93 (s, 3H).

Step 7

[2-Methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]thiazol-7-yl]methanamine(Compound 156-7)

Compound 156-7 (0.03 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 156-6, and used as it isin the next reaction.

¹H NMR (300 MHz, DMSO-d₆, δ): 7.68 (d, J=7.8 Hz, 2H), 7.42 (d, J=8.4 Hz,1H), 7.22 (d, J=8.4 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.97 (s, 2H), 2.72(s, 3H).

Step 8

N-([2-Methyl-4-{4-(trifluoromethyl)phenoxy}benzo[d]thiazol-7-yl]methyl)acrylamide(Compound 256)

Compound 256 (0.075 g, 37% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 156-7.

¹H NMR (400 MHz, DMSO-d₅, δ): 8.76 (br, 1H), 7.69 (d, J=8.4 Hz, 2H),7.39 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H),6.30 (dd, J=17.2, 10.0 Hz, 1H), 6.19-6.15 (m, 1H), 5.67 (dd, J=10.0, 1.6Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.75 (s, 3H);

ESIMS m/z: [M+]⁺ 393.

Example 157

Step 1

N-(2-Bromo-5-methoxyphenyl)ethane thioamide (Compound 157-1)

N-(2-Bromo-5-methoxyphenyl)acetamide (6.0 g, 24.69 mmol) was dissolvedin 1,4-dioxane (50 mL), and2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (9.98g, 24.69 mmol) was added to the solution. The mixture was stirred at100° C. for 5 hours. The mixture was left to cool to room temperatureand water was added to the mixture. The organic layer was extracted withethyl acetate, washed with water, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=90/10)to obtain compound 157-1 (4.0 g, 63%).

¹H NMR (500 MHz, CDCl₃, δ): 9.03-8.83 (m, 1H), 8.42 (d, J=3.1 Hz, 1H),7.48 (d, J=8.9 Hz, 1H), 6.72 (dd, J=8.9, 3.1 Hz, 1H), 3.81 (s, 3H), 2.79(s, 3H); ESIMS m/z: [M+]⁺ 260.

Step 2

4-Bromo-7-methoxy-2-methylbenzo[d]thiazole (Compound 157-2)

Compound 157-1 (4.0 g, 15.44 mmol) was dissolved in water (80 mL), andsodium hydroxide (12.35 g, 308.88 mmol) was added to the solution. Themixture was stirred at room temperature for 15 minutes. An aqueoussolution (80 mL) of potassium ferricyanide (20.34 g, 61.77 mmol) wasadded dropwise to the mixture under ice cooling. The mixture was stirredat 0° C. for 2 hours. The mixture was filtered, and the residue obtainedwas washed with iced water, and dried under reduced pressure to obtain acrude product. The crude product was purified by reverse-phase columnchromatography [REVELERIS® C18 column, 40 μm silica, acetonitrile/water(65/35)] to obtain compound 157-2 (2.0 g, 50%).

¹H NMR (400 MHz, CDCl₃, δ): 7.56 (dd, J=8.6, 0.7 Hz, 1H), 6.69 (d, J=8.3Hz, 1H), 3.96 (s, 3H), 2.88 (d, J=0.7 Hz, 3H);

ESIMS m/z: [M+H]⁺ 258.

Step 3

4-Bromo-2-methylbenzo[d]thiazol-7-ol (Compound 157-3)

Compound 157-3 (1.1 g, 58%) was obtained in the same manner as step 4 ofexample 144, using compound 157-2.

¹H NMR (500 MHz, CDCl₃, δ): 7.48 (d, J=8.2 Hz, 1H), 6.67 (d, J=8.5 Hz,1H), 3.96 (s, 1H), 2.88 (d, J=6.0 Hz, 3H); ESIMS m/z: [M+H]⁺ 244.

Step 4

4-Bromo-2-methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]thiazole(Compound 157-4)

Compound 157-4 (0.550 g, 32%) was obtained in the same manner as step 1of example 3, using compound 157-3.

¹H NMR (400 MHz, CDCl₃, 6): 7.64-7.60 (m, 3H), 7.12-7.08 (m, 2H), 6.87(d, J=8.0 Hz, 1H), 2.88 (d, J=6.0 Hz, 3H);

ESIMS m/z: [M+H]⁺ 388.

Step 5

2-Methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]thiazole-4-carbonitrile(Compound 157-5)

Compound 157-5 (0.220 g, 46%) was obtained in the same manner as step 6of example 144, using compound 157-4.

¹H NMR (400 MHz, CDCl₃, δ): 7.73 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz,2H), 7.21 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.3 Hz, 1H), 2.93 (s, 3H);

ESIMS m/z: [M+H]⁺ 335.

Step 6

[2-Methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]thiazol-4-yl]methanamine(Compound 157-6)

Compound 157-6 (0.200 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 157-5, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 339.

Step 7

N-([2-Methyl-7-{4-(trifluoromethyl)phenoxy}benzo[d]thiazol-4-yl]methyl)acrylamide(Compound 257)

Compound 257 (0.064 g, 28% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 157-6.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.67 (t, J=5.8 Hz, 1H), 7.75 (d, J=8.5 Hz,2H), 7.41 (d, J=8.2 Hz, 1H), 7.18 (dd, J=11.9, 8.2 Hz, 3H), 6.34 (dd,J=17.1, 10.4 Hz, 1H), 6.14 (dd, J=17.2, 2.3 Hz, 1H), 5.63 (dd, J=10.2,2.3 Hz, 1H), 4.81 (d, J=5.8 Hz, 2H), 2.83 (s, 3H);

ESIMS m/z: [M+H]⁺ 393.

Example 158

Step 1

6-Bromo-3-(hydroxyimino)-2,3-dihydrobenzo[b]thiophene-1,1-dioxide(Compound 158-1)

To a methanol solution (4.9 mL) of6-bromobenzo[b]thiophene-3(2H)-on-1,1-dioxide (128 mg, 0.49 mmol)obtained by a well-known method (WO2014/146493), sodium acetate (201 mg,2.45 mmol) and hydroxylamine hydrochloride (170 mg, 2.45 mmol) wereadded at room temperature, and the mixture was refluxed for 1 hour. Themixture was left to cool to room temperature and water was added to themixture. The organic layer was extracted with ethyl acetate. The organiclayer obtained was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtaincompound 158-1 as a crude product, which was used as it is in the nextreaction.

ESIMS m/z: [M−H]⁻ 274, 276.

Step 2

3-Amino-6-bromo-2,3-dihydrobenzo[b]thiophen-1,1-dioxide (Compound 158-2)

To a methanol solution (2.5 mL) of compound 158-1 (135 mg, 0.49 mmol),zinc powder (160 mg, 2.45 mmol) and an aqueous hydrochloric acidsolution (6 mol/L, 1 mL) were added at room temperature, and the mixturewas stirred at 60° C. for 2 hours. The mixture was cooled in ice bath,and then neutralized with an aqueous sodium hydrogen carbonate solution.The organic layer was extracted with ethyl acetate, washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain compound 158-2 as a crude product,which was used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 262, 264.

Step 3

N-(6-Bromo-1,1-dioxide-2,3-dihydrobenzo[b]thiophen-3-yl)acrylamide(Compound 158-3)

Compound 158-3 (99 mg, 91% over three steps) was obtained in the samemanner as step 3 of example 17, using compound 158-2.

¹H-NMR (400 MHz, DMSO-d₆, δ): 8.95 (d, J=7.7 Hz, 1H), 8.13 (d, J=1.8 Hz,1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 6.27 (dd,J=17.2, 9.5 Hz, 1H), 6.19 (dd, J=17.2, 2.7 Hz, 1H), 5.71 (dd, J=9.3, 2.9Hz, 1H), 5.65 (q, J=6.9 Hz, 1H), 4.09 (dd, J=13.6, 7.7 Hz, 1H), 3.50(dd, J=13.8, 5.7 Hz, 1H);

ESIMS m/z: [M−H]⁻ 314, 316.

Step 4

N-[1,1-Dioxide-6-{4-(trifluoromethyl)phenoxy}-2,3-dihydrobenzo[b]thiophen-3-yl]acrylamide(Compound 258)

Compound 158-3 (34.0 mg, 0.108 mmol) was dissolved in 1,4-dioxane (1.0mL), and 4-(trifluoromethyl)phenol (34.9 mg, 0.215 mmol), cesiumcarbonate (123 mg, 0.376 mmol), dimethylglycine (5.5 mg, 0.054 mmol) andcopper(I) iodide (5.1 mg, 0.027 mmol) were added to the solution. Themixture was refluxed for 1 hour. The mixture was left to cool to roomtemperature, and a saturated ammonium chloride aqueous solution wasadded to the mixture. The organic layer was extracted with ethylacetate, washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (heptane/ethylacetate=90/10→50/50) to obtain a crude product. The crude productobtained was purified using a preparative HPLC [Waters Xbridge Prep C18OBD column, 5 μm silica, diameter 19 mm, length 100 mm;acetonitrile/0.05% aqueous TFA solution (30/70→40/60)] to obtaincompound 258 (11 mg, 26%).

¹H-NMR (400 MHz, CDCl₃, δ): 7.65 (d, J=8.2 Hz, 2H), 7.57 (d, J=7.7 Hz,1H), 7.32-7.29 (m, 2H), 7.12 (d, J=8.2 Hz, 2H), 6.37 (d, J=16.8 Hz, 1H),6.25-6.22 (m, 1H), 6.07 (dd, J=17.0, 10.6 Hz, 1H), 5.92-5.90 (m, 1H),5.75 (d, J=10.0 Hz, 1H), 3.85 (dd, J=14.3, 7.5 Hz, 1H), 3.44 (dd,J=14.0, 2.7 Hz, 1H);

ESIMS m/z: [M−H]⁻ 396.

Example 159

Step 1

7-{4-(Trifluoromethyl)phenoxy}-2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-one(Compound 159-1)

7-Chloro-2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-one (130 mg, 0.708 mmol)obtained by a well-known method (Bioorganic & Medicinal ChemistryLetters, 2011, 21, 1402.) was dissolved in DMF (0.7 mL), and4-(trifluoromethyl)phenol (115 mg, 0.708 mmol), triethylamine (0.148 mL,1.06 mmol) and 1,4-diazabicyclo[2,2,2]octane (15.9 mg, 0.142 mmol) wereadded to the solution at room temperature. The mixture was stirred for 3hours. Saturated saline was added to the mixture. The organic layer wasextracted with ethyl acetate. The organic layer obtained was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=95/5→65/35) to obtain compound159-1 (150 mg, 69%).

¹H-NMR (400 MHz, CDCl₃, δ) 8.29 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.1 Hz,2H), 7.28 (d, J=8.2 Hz, 2H), 6.72 (d, J=8.2 Hz, 1H), 4.60 (t, J=6.6 Hz,2H), 2.80 (t, J=6.3 Hz, 2H);

ESIMS m/z: [M+H]⁺ 310.

Step 2

7-{4-(Trifluoromethyl)phenoxy}-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-amine(Compound 159-2)

Compound 159-1 (126 mg, 0.407 mmol) was dissolved in methanol (8.0 mL),and ammonium acetate (314 mg, 4.07 mmol) and sodium cyanoborohydride(51.2 mg, 0.814 mmol) were added to the solution at room temperature.The mixture was refluxed overnight. The mixture was left to cool to roomtemperature and a saturated sodium bicarbonate aqueous solution wasadded to the mixture. The organic layer was extracted with ethylacetate. The organic layer obtained was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to obtain compound 159-2 as a crude product, which was used asit is in the next reaction.

ESIMS m/z: [M+H]⁺ 311.

Step 3

N-[7-{4-(Trifluoromethyl)phenoxy}-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]acrylamide(Compound 259)

Compound 259 (51 mg, 36% over two steps) was obtained in the same manneras step 3 of example 17, using compound 159-2.

¹H-NMR (400 MHz, CDCl₃, δ): 7.66-7.61 (m, 3H), 7.22 (d, J=8.6 Hz, 2H),6.60 (d, J=7.7 Hz, 1H), 6.38 (d, J=16.8 Hz, 1H), 6.10 (dd, J=16.8, 9.5Hz, 1H), 5.78-5.72 (m, 2H), 5.29-5.24 (m, 1H), 4.42-4.36 (m, 1H),4.32-4.26 (m, 1H), 2.28-2.20 (m, 1H), 2.13-2.05 (m, 1H);

ESIMS m/z: [M+H]⁺ 365.

Example 160

Step 1

3-Bromo-2-[{(2-hydroxyethyl)(methyl)amino}methyl]-6-methoxyphenol(Compound 160-1)

Commercially available 6-bromo-2-hydroxy-3-methoxybenzaldehyde (0.50 g,2.16 mmol) was dissolved in methanol (21.6 mL), and2-(methylamino)ethan-1-ol (0.24 g, 3.25 mmol) and acetic acid (0.012 mL,0.22 mmol) were added to the solution. The mixture was stirred at 50° C.for 1.5 hours. The mixture was cooled to room temperature, and sodiumborohydride (0.25 g, 6.49 mmol) was added to the mixture. The mixturewas stirred for 30 minutes. The mixture was concentrated under reducedpressure, and a saturated sodium bicarbonate aqueous solution was addedto the residue. The organic layer was extracted with ethyl acetate,washed with saturated saline, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure to obtain compound 160-1 (0.62g) as a crude product, which was used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 290.

Step 2

6-Bromo-9-methoxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(Compound 160-2)

Compound 160-1 and triphenylphosphine (0.85 g, 3.25 mmol) were dissolvedin THF (21 mL), and the solution was cooled to 0° C. Diisopropylazodicarboxylate (0.63 mL, 3.25 mmol) was added to the solution, and thesolution was stirred at room temperature overnight. The mixture wasconcentrated under reduced pressure, and a 2 mol/L aqueous hydrochloricacid solution was added to the residue. The mixture was washed withethyl acetate. A 4 mol/L aqueous sodium hydroxide solution was added tothe aqueous layer, and the organic layer was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to obtain compound 160-2 (93.0 mg, 98% over two steps).

¹H-NMR (400 MHz, CDCl₃, δ): 7.23 (d, J=9.0 Hz, 1H), 6.70 (d, J=9.0 Hz,1H), 4.14-4.13 (m, 2H), 4.07 (s, 2H), 3.84 (s, 3H), 3.04-3.03 (m, 2H),2.44 (s, 3H); ESIMS m/z: [M+H]³⁰ 272.

Step 3

6-Bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-ol, bromate(Compound 160-3)

Compound 160-3 (285 mg) was obtained as a crude product in the samemanner as step 1 of example 19, using compound 160-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 258.

Step 4

6-Bromo-4-methyl-9-{4-(trifluoromethyl)phenoxy}-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(Compound 160-4)

Compound 160-3 (50.0 mg, 0.15 mmol) was dissolved in DMA (1 mL), andcesium carbonate (144 mg, 0.44 mmol) and1-fluoro-4-(trifluoromethyl)benzene were added to the solution. Themixture was stirred at 120° C. overnight. Water was added to themixture. The organic layer was extracted with ethyl acetate, washed withsaturated saline, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform/methanol=100/0→95/5) to obtaincompound 160-4 (31.1 mg, 21% over two steps).

¹H-NMR (400 MHz, CDCl₃, δ): 7.54 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz,1H), 6.96 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 1H), 4.08 (s, 2H),3.93-3.92 (m, 2H), 2.96-2.95 (m, 2H), 2.46 (s, 3H);

ESIMS m/z: [M+H]⁺ 402.

Step 5

4-Methyl-9-{4-(trifluoromethyl)phenoxy}-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-6-carbonitrile(Compound 160-5)

Compound 160-5 (16.3 mg, 61%) was obtained in the same manner as step 1of example 54, using compound 160-4.

¹H-NMR (400 MHz, CDCl₃, δ): 7.60 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.1 Hz,1H), 7.02 (d, J=8.1 Hz, 3H), 4.05 (s, 2H), 3.96-3.94 (m, 2H), 3.01-2.99(m, 2H), 2.49 (s, 3H);

ESIMS m/z: [M+H]⁺ 349.

Step 6

[4-Methyl-9-{4-(trifluoromethyl)phenoxy}-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-6-yl]methanamine(Compound 160-6)

Compound 160-6 was obtained as a crude product in the same manner asstep 1 of example 86, using compound 160-5, and used as it is in thenext reaction.

ESIMS m/z: [M+H]⁺ 353.

Step 7

N-([4-Methyl-9-{4-(trifluoromethyl)phenoxy}-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-yl]methyl)acrylamide(Compound 260)

Compound 260 (2.2 mg, 12% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 160-6.

¹H-NMR (400 MHz, CDCl₃, δ): 7.54 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.1 Hz,1H), 6.98 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.37 (dd, J=16.8,1.6 Hz, 1H), 6.15 (dd, J=16.6, 10.3 Hz, 1H), 6.09 (br, 1H), 5.70 (dd,J=10.3, 1.3 Hz, 1H), 4.57 (d, J=4.9 Hz, 2H), 3.90-3.89 (m, 2H), 3.71 (s,2H), 2.90-2.88 (m, 2H), 2.44 (s, 3H);

ESIMS m/z: [M+H]⁺ 407.

Example 161

Step 1

Ethyl 4-[3-{4-(trifluoromethyl)phenoxy}phenoxy]butanoate (Compound161-1)

3-{4-(trifluoromethyl)phenoxy}phenol (300 mg, 1.18 mmol) obtained by awell-known method (Bioorganic & Medicinal Chemistry Letters, 2015, 23,3322.) was dissolved in acetone (8.0 mL), and potassium carbonate (489mg, 3.54 mmol) and ethyl 4-bromobutyrate (0.20 mL, 1.42 mmol) were addedto the solution at room temperature. The mixture was refluxed for 2hours. The reaction mixture was left to cool to room temperature andwater was added to the mixture. The organic layer was extracted withethyl acetate. The organic layer obtained was washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=95/5→80/20) to obtain compound161-1 (320 mg, 74%).

¹H-NMR (400 MHz, CDCl₃, δ): 7.57 (d, J=9.1 Hz, 2H), 7.26 (t, J=8.4 Hz,1H), 7.06 (d, J=8.6 Hz, 2H), 6.71 (dd, J=7.9, 2.0 Hz, 1H), 6.63 (dd,J=7.9, 2.0 Hz, 1H), 6.58-6.58 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.98 (t,J=5.9 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.14-2.07 (m, 2H), 1.25 (t, J=7.2Hz, 3H).

Step 2

4-[3-{4-(Trifluoromethyl)phenoxy}phenoxy]butanoic acid (Compound 161-2)

Compound 161-1 (320 mg, 0.869 mmol) was dissolved in a mixed solvent oftetrahydrofuran (0.87 mL), distilled water (0.43 mL) and ethanol (0.87mL). Lithium hydroxide monohydrate (72.9 mg, 1.74 mmol) was added to thesolution at room temperature. The mixture was stirred for 2 hours. Themixture was concentrated under reduced pressure. A 2 mol/L hydrochloricacid aqueous solution was added to the residue obtained while theresidue was cooled in ice bath. The solid was filtered off, washed withwater, and dried under reduced pressure to obtain compound 161-2 (254mg, 86%).

¹H-NMR (400 MHz, DMSO-d₆, δ): 7.74 (d, J=9.1 Hz, 2H), 7.35 (t, J=8.4 Hz,1H), 7.15 (d, J=9.1 Hz, 2H), 6.82 (dd, J=8.2, 2.3 Hz, 1H), 6.71 (t,J=2.3 Hz, 1H), 6.67 (dd, J=7.7, 2.3 Hz, 1H), 3.98 (t, J=6.6 Hz, 2H),2.37 (t, J=7.2 Hz, 2H), 1.95-1.88 (m, 2H);

ESIMS m/z: [M−H]⁻ 339.

Step 3

8-{4-(Trifluoromethyl)phenoxy}-3,4-dihydrobenzo[b]oxepin-5(2H)-one(Compound 161-3)

To compound 161-2 (120 mg, 0.353 mmol), Eaton's reagent (phosphoruspentoxide/methanesulfonic acid, CAS No: 39394-84-8) (0.3 mL) was addeddropwise at room temperature. The mixture was stirred at 80° C. for 1hour. The mixture was left to cool to room temperature and addeddropwise in iced water. The organic layer was extracted with ethylacetate. The organic layer obtained was washed with saturated saline,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(heptane/ethyl acetate=95/5→70/30) to obtain compound 161-3 (85 mg,75%).

¹H-NMR (400 MHz, CDCl₃, δ): 7.81 (d, J=9.1 Hz, 1H), 7.65 (d, J=9.5 Hz,2H), 7.15 (d, J=8.6 Hz, 2H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.66 (d,J=2.3 Hz, 1H), 4.25 (t, J=6.6 Hz, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.26-2.19(m, 2H).

Step 4

8-{4-(Trifluoromethyl)phenoxy}-2,3,4,5-tetrahydrobenzo[b]oxepin-5-amine(Compound 161-4)

Compound 161-4 was obtained as a crude product in the same manner asstep 2 of example 159, using compound 161-3, and used as it is in thenext reaction.

ESIMS m/z: [M−H]⁻ 322.

Step 5

N-[8-{4-(Trifluoromethyl)phenoxy}-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl]acrylamide(Compound 261)

Compound 261 (11 mg, 12% over two steps) was obtained in the same manneras step 3 of example 17, using compound 161-4.

¹H-NMR (400 MHz, CDCl₃, δ): 7.59 (d, J=7.7 Hz, 2H), 7.28-7.25 (m, 1H),7.07 (d, J=8.6 Hz, 2H), 6.74-6.71 (m, 2H), 6.32 (dd, J=17.4, 1.6 Hz,1H), 6.25 (br, 1H), 6.12 (dd, J=16.5, 10.2 Hz, 1H), 5.67 (dd, J=10.2,1.6 Hz, 1H), 5.35-5.31 (m, 1H), 4.41-4.36 (m, 1H), 3.75 (m, 1H),2.28-2.23 (m, 2H), 1.91-1.74 (m, 2H);

ESIMS m/z: [M+H]⁺ 378.

Example 162

Step 1

5-Bromobenzofuran-3(2H)-one oxime (Compound 162-1)

Compound 162-1 was obtained as a crude product in the same manner asstep 1 of example 158, using commercially available5-bromobenzofuran-3(2H)-one (200 mg, 0.94 mmol), and was used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 228, 230.

Step 2

5-Bromo-2,3-dihydrobenzofuran-3-amine (Compound 162-2)

Compound 162-2 was obtained as a crude product in the same manner asstep 2 of example 158, using compound 162-1, and used as it is in thenext reaction.

Step 3

N-(5-Bromo-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound 162-3)

Compound 162-3 (75 mg, 30% over three steps) was obtained in the samemanner as step 3 of example 17, using compound 162-2.

¹H-NMR (400 MHz, CDCl₃, δ): 7.45 (d, J=2.3 Hz, 1H), 7.35 (dd, J=8.4, 2.0Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 6.35 (d, J=17.0 Hz, 1H), 6.07 (dd,J=16.8, 10.0 Hz, 1H), 5.82 (br, 1H), 5.73 (d, J=10.2 Hz, 1H), 5.69-5.67(m, 1H), 4.76 (dd, J=10.2, 7.9 Hz, 1H), 4.39 (dd, J=10.2, 4.3 Hz, 1H);

ESIMS m/z: [M−H]⁻ 266, 268.

Step 4

N-{5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl}acrylamide(Compound 162-4)

Compound 162-3 (75 mg, 0.280 mmol) was dissolved in DMF (1.1 mL), andpotassium acetate (96 mg, 0.979 mmol), bis(pinacolato)diboron (213 mg,0.839 mmol) and{1,1′-bis(diphenylphosphino)ferrocene}palladium(II)dichloridedichloromethane adduct (22.8 mg, 0.028 mmol) were added to the solutionat room temperature. The mixture was stirred under Ar atmosphere at 80°C. for 2 hours. The mixture was left to cool to room temperature andwater was added to the mixture. The organic layer was extracted withethyl acetate. The organic layer obtained was washed with saturatedsaline, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=90/10→30/70) to obtain compound162-4 as a crude product, which was used as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 316.

Step 5

N-(5-Hydroxy-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound 162-5)

Compound 162-4 was dissolved in THF (0.300 mL), and an aqueous hydrogenperoxide solution (30%, 0.113 mL) was added dropwise to the solution at0° C. The temperature of the mixture was raised to room temperature, andthe mixture was stirred for 1 hour. After the mixture was cooled in icebath, a saturated sodium thiosulfate aqueous solution was added to themixture. The organic layer was extracted with ethyl acetate. The organiclayer obtained was washed with saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (heptane/ethylacetate=90/10→50/50) to obtain compound 162-5 (8 mg, 14% over twosteps).

¹H-NMR (400 MHz, CD₃OD, δ): 6.77-6.76 (m, 1H), 6.65-6.63 (m, 2H),6.26-6.23 (m, 2H), 5.68 (dd, J=8.8, 3.4 Hz, 1H), 5.55 (dd, J=8.4, 3.9Hz, 1H), 4.63 (dd, J=9.5, 8.2 Hz, 1H), 4.23 (dd, J=10.0, 4.5 Hz, 1H);

ESIMS m/z: [M−H]⁻ 204

Step 6

N-[5-{4-(Trifluoromethyl)phenoxy}-2,3-dihydrobenzofuran-3-yl]acrylamide(Compound 262)

Compound 262 (11 mg, 92%) was obtained in the same manner as step 3 ofexample 1, using compound 162-5 (7 mg, 0.034 mmol).

¹H-NMR (400 MHz, CDCl₃, δ): 7.55 (d, J=8.2 Hz, 2H), 7.07 (d, J=2.7 Hz,1H), 6.99-6.96 (m, 3H), 6.88 (d, J=9.1 Hz, 1H), 6.34 (d, J=16.8 Hz, 1H),6.07 (dd, J=17.0, 10.2 Hz, 1H), 5.90-5.87 (br m, 1H), 5.72-5.68 (m, 2H),4.80 (dd, J=9.7, 7.9 Hz, 1H), 4.42 (dd, J=10.4, 4.1 Hz, 1H);

ESIMS m/z: [M+H]⁺ 350.

Example 163

Step 1

1-(3-Bromo-2-hydroxy-5-methoxyphenyl)-2-chloroethan-1-one (Compound163-1)

1-(3-Bromo-2-hydroxy-5-methoxyphenyl)ethan-1-one (0.545 g, 2.22 mmol)obtained by a well-known method (Tetrahedron, 2008, 64, 3471.) wasdissolved in a mixed solvent of dichloroethane (31.8 mL) and methanol(12.7 mL), and benzyltrimethylammonium dichloroiodate (1.55 g, 4.45mmol) was added to the solution at room temperature. The mixture wasstirred at 80° C. for 3 hours. The mixture was left to cool to roomtemperature and a 5% sodium hydrogensulfite aqueous solution was addedto the mixture. The organic layer was extracted with ethyl acetate. Theorganic layer obtained was washed with saturated saline, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toobtain compound 163-1 as a crude product, which was used as it is in thenext reaction.

ESIMS m/z: [M−H]⁻ 277, 279.

Step 2

1-(3-Bromo-2,5-dihydroxyphenyl)-2-chloroethan-1-one (Compound 163-2)

Compound 163-1 was dissolved in dichloromethane (4.0 mL), and a 1 mol/Lboron tribromide dichloromethane solution (2.5 mL, 2.50 mmol) was addeddropwise to the solution at −78° C. The mixture was stirred for 30minutes at −78° C. The temperature of the mixture was raised to roomtemperature, and the mixture was stirred for 1 hour. The mixture wasadded dropwise to iced water, and then stirred for 10 minutes. Theorganic layer was extracted with chloroform. The organic layer obtainedwas washed with saturated saline, dried over anhydrous sodium sulfate,and concentrated under reduced pressure to obtain compound 163-2 as acrude product, which was used as it is in the next reaction.

ESIMS m/z: [M−H]⁻ 263, 265.

Step 3

7-Bromo-5-hydroxybenzofuran-3(2H)-one (Compound 163-3)

Compound 163-2 was dissolved in ethanol (6.7 mL), and sodium acetate(116 mg, 1.41 mmol) was added to the solution at room temperature. Thesolution was refluxed for 1 hour. The mixture was left to cool to roomtemperature and water was added to the mixture. The organic layer wasextracted with ethyl acetate. The organic layer obtained was washed withsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (heptane/ethyl acetate=90/10→50/50) to obtain compound163-3 (85 mg, 17% over three steps).

¹H-NMR (400 MHz, DMSO-d₆, δ): 7.42 (d, J=2.3 Hz, 1H), 6.90 (d, J=1.8 Hz,1H), 4.87 (s, 2H);

ESIMS m/z: [M−H]⁻ 227, 229.

Step 4

7-Bromo-5-hydroxybenzofuran-3(2H)-one oxime (Compound 163-4)

Compound 163-4 was obtained as a crude product in the same manner asstep 1 of example 158, using compound 163-3 (55 mg, 0.24 mmol), and usedas it is in the next reaction.

ESIMS m/z: [M−H]⁻ 242, 244.

Step 5

3-Amino-7-bromo-2,3-dihydrobenzofuran-5-ol (Compound 163-5)

Compound 163-5 was obtained as a crude product in the same manner asstep 2 of example 158, using compound 163-4, and used as it is in thenext reaction.

Step 6

N-(7-Bromo-5-hydroxy-2,3-dihydrobenzofuran-3-y)acrylamide (Compound163-6)

To a solution of compound 163-5 in DMA (2.0 mL), triethylamine (0.100mL) and acryloyl chloride (0.058 mL, 0.72 mmol) were added at roomtemperature. The mixture was stirred at room temperature for 1 hour.After confirmation of vanishment of the raw materials, potassiumcarbonate (166 mg, 1.2 mmol) and methanol (1.00 mL) were added to thereaction mixture. The mixture was stirred at 80° C. for 1 hour. Thereaction mixture was cooled to room temperature and water was added tothe mixture. The organic layer was extracted with ethyl acetate, andwashed with saturated saline. The organic layer obtained was dried overanhydrous sodium sulfate, insolubles were filtered out, and the organiclayer was concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (heptane/ethylacetate=90/10→50/50) to obtain a crude product 163-6, which was used asit is in the next reaction.

ESIMS m/z: [M−H]⁻ 282, 284.

Step 7

N-[7-Bromo-5-{4-(trifluoromethyl)phenoxy}-2,3-dihydrobenzofuran-3-yl]acrylamide(Compound 263)

Compound 263 (27 mg, 26% over four steps) was obtained in the samemanner as step 3 of example 1, using compound 163-6.

¹H-NMR (400 MHz, CDCl₃, δ): 7.58 (d, J=8.2 Hz, 2H), 7.18 (d, J=1.8 Hz,1H), 7.05 (d, J=2.3 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H), 6.35 (d, J=17.2 Hz,1H), 6.06 (dd, J=17.0, 10.6 Hz, 1H), 5.89-5.86 (br, 1H), 5.85-5.79 (m,1H), 5.74 (d, J=9.1 Hz, 1H), 4.89 (dd, J=10.2, 7.9 Hz, 1H), 4.50 (dd,J=10.4, 4.1 Hz, 1H);

ESIMS m/z: [M−H]⁻ 426, 428.

Example 164

Step 1

7-Bromobenzofuran-3(2H)-one oxime (Compound 164-1)

Compound 164-1 was obtained as a crude product in the same manner asstep 1 of example 158, using commercially available7-bromobenzofuran-3(2H)-one (300 mg, 1.41 mmol), and was used as it isin the next reaction.

ESIMS m/z: [M−H]⁻ 226, 228.

Step 2

7-Bromo-2,3-dihydrobenzofuran-3-amine (Compound 164-2)

Compound 164-2 was obtained as a crude product in the same manner asstep 2 of example 158, using compound 164-1, and used as it is in thenext reaction.

Step 3

N-(7-Bromo-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound 164-3)

Compound 164-3 (160 mg, 46% over three steps) was obtained in the samemanner as step 3 of example 17, using compound 164-2.

¹H-NMR (400 MHz, CDCl₃, δ): 7.43 (d, J=7.2 Hz, 1H), 7.29 (d, J=7.2 Hz,1H), 6.84 (t, J=7.9 Hz, 1H), 6.34 (d, J=17.1 Hz, 1H), 6.07 (dd, J=17.3,10.5 Hz, 1H), 5.92-5.86 (m, 1H), 5.81-5.75 (m, 1H), 5.73 (dd, J=10.3,1.3 Hz, 1H), 4.83 (dd, J=10.3, 8.1 Hz, 1H), 4.48 (dd, J=10.3, 3.6 Hz,1H);

ESIMS m/z: [M−H]⁻ 266, 268.

Step 4

N-{7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl}acrylamide(Compound 164-4)

Compound 164-4 was obtained as a crude product in the same manner asstep 4 of example 162, using compound 164-3, and used as it is in thenext reaction.

ESIMS m/z: [M+H]⁺ 316.

Step 5

N-(7-Hydroxy-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound 164-5)

Compound 164-5 (10 mg, 9% over two steps) was obtained in the samemanner as step 5 of example 162, using compound 164-4.

¹H-NMR (400 MHz, CDCl₃, δ): 6.91-6.82 (m, 3H), 6.34 (dd, J=16.8, 1.4 Hz,1H), 6.07 (dd, J=17.0, 10.2 Hz, 1H), 5.70-5.67 (m, 3H), 4.77 (dd,J=10.0, 7.7 Hz, 1H), 4.44 (dd, J=10.4, 3.6 Hz, 1H);

ESIMS m/z: [M−H]⁻ 204.

Step 6

N-[7-{4-(Trifluoromethyl)phenoxy}-2,3-dihydrobenzofuran-3-yl]acrylamide(Compound 264)

Compound 264 (11 mg, 65%) was obtained in the same manner as step 3 ofexample 1, using compound 164-5 (10 mg, 0.049 mmol).

¹H-NMR (400 MHz, CDCl₃, δ): 7.57 (d, J=8.2 Hz, 2H), 7.22 (d, J=7.2 Hz,1H), 7.04-7.00 (m, 3H), 6.96 (t, J=7.5 Hz, 1H), 6.36 (dd, J=16.5, 1.1Hz, 1H), 6.09 (dd, J=16.8, 10.4 Hz, 1H), 5.92 (br, 1H), 5.79-5.70 (m,2H), 4.78 (dd, J=10.2, 7.9 Hz, 1H), 4.42 (dd, J=10.4, 4.1 Hz, 1H);

ESIMS m/z: [M+H]⁺ 350.

Example 165

Step 1

6-Bromobenzofuran-3(2H)-one oxime (Compound 165-1)

Compound 165-1 was obtained as a crude product in the same manner asstep 1 of example 158, using commercially available7-bromobenzofuran-3(2H)-one (300 mg, 1.41 mmol), and was used as it isin the next reaction.

ESIMS m/z: [M−H]⁻ 226, 228.

Step 2

6-Bromo-2,3-dihydrobenzofuran-3-amine (Compound 165-2)

Compound 165-2 was obtained as a crude product in the same manner asstep 2 of example 158, using compound 165-1, and used as it is in thenext reaction.

Step 3

N-(6-Bromo-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound 165-3)

Compound 165-3 (110 mg, 33% over three steps) was obtained in the samemanner as step 3 of example 17, using compound 165-2.

¹H-NMR (400 MHz, CDCl₃, δ): 7.20 (d, J=8.2 Hz, 1H), 7.09-7.00 (m, 2H),6.38-6.34 (m, 1H), 6.07-6.03 (m, 1H), 5.84-5.80 (m, 1H), 5.75-5.72 (m,1H), 5.64 (m, 1H), 4.76 (dd, J=10.0, 7.7 Hz, 1H), 4.40 (dd, J=10.2, 3.9Hz, 1H);

ESIMS m/z: [M−H]⁻ 266, 268.

Step 4

N-{6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl}acrylamide(Compound 165-4)

Compound 165-4 was obtained as a crude product in the same manner asstep 4 of example 162, using compound 165-3, and used as it is in thenext reaction.

ESIMS m/z: [M+H]⁺ 316.

Step 5

N-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound 165-5)

Compound 165-5 (13 mg, 21% over two steps) was obtained in the samemanner as step 5 of example 162, using compound 165-4.

¹H-NMR (400 MHz, CD₃OD, δ): 7.11 (d, J=7.7 Hz, 1H), 6.35 (dd, J=8.2, 2.3Hz, 1H), 6.26-6.20 (m, 3H), 5.66 (dd, J=8.6, 3.2 Hz, 1H), 5.47 (dd,J=7.9, 3.9 Hz, 1H), 4.65 (dd, J=10.0, 7.7 Hz, 1H), 4.28 (dd, J=10.0, 4.1Hz, 1H);

ESIMS m/z: [M−H]⁻ 204

Step 6

N-{6-[4-(Trifluoromethyl)phenoxy]-2,3-dihydrobenzofuran-3-yl}acrylamide(Compound 265)

Compound 265 (10 mg, 47%) was obtained in the same manner as step 3 ofexample 1, using compound 165-5 (13 mg, 0.063 mmol).

¹H-NMR (400 MHz, CDCl₃, δ): 7.59 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz,1H), 7.07 (d, J=8.6 Hz, 2H), 6.62 (dd, J=8.2, 2.3 Hz, 1H), 6.56 (d,J=2.3 Hz, 1H), 6.35 (dd, J=16.8, 1.4 Hz, 1H), 6.08 (dd, J=16.8, 10.4 Hz,1H), 5.92-5.84 (br, 1H), 5.73 (dd, J=10.4, 0.9 Hz, 1H), 5.67-5.65 (m,1H), 4.79 (dd, J=10.0, 7.7 Hz, 1H), 4.44 (dd, J=10.2, 3.4 Hz, 1H).

ESIMS m/z: [M+H]⁺ 350.

Example 166

Step 1

1-(5-Bromo-2-hydroxy-4-methylphenyl)-2-chloroethan-1-one (Compound166-1)

Compound 166-1 was obtained as a crude product in the same manner asstep 1 of example 163, using commercially available1-(5-bromo-2-hydroxy-4-methylphenyl)ethan-1-one (1.00 g, 4.37 mmol), andused as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 263, 265.

Step 2

5-Bromo-6-methylbenzofuran-3(2H)-one (Compound 166-2)

Compound 166-2 (0.750 g, 76%) was obtained in the same manner as step 3of example 163, using compound 166-1.

¹H-NMR (400 MHz, CDCl₃, δ): 7.83 (s, 1H), 7.06 (s, 1H), 4.64 (s, 2H),2.48 (s, 3H),

ESIMS m/z: [M+H]⁺ 227, 229.

Step 3

5-Bromo-6-methylbenzofuran-3(2H)-one oxime (Compound 166-3)

Compound 166-3 was obtained as a crude product in the same manner asstep 1 of example 158, using compound 166-2 (200 mg, 0.881 mmol), andused as it is in the next reaction.

ESIMS m/z: [M+H]⁺ 242, 244.

Step 4

5-Bromo-6-methyl-2,3-dihydrobenzofuran-3-amine (Compound 166-4)

Compound 166-4 was obtained as a crude product in the same manner asstep 2 of example 158, using compound 166-3, and used as it is in thenext reaction.

Step 5

N-(5-Bromo-6-methyl-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound166-5)

Compound 166-5 (110 mg, 44% over three steps) was obtained in the samemanner as step 3 of example 17, using compound 166-4.

¹H-NMR (400 MHz, CDCl₃, δ): 7.47 (s, 1H), 6.77 (s, 1H), 6.34 (dd,J=16.8, 1.4 Hz, 1H), 6.06 (dd, J=17.2, 10.4 Hz, 1H), 5.90-5.84 (br, 1H),5.72 (dd, J=10.4, 1.4 Hz, 1H), 5.63-5.61 (m, 1H), 4.73 (dd, J=10.2, 7.9Hz, 1H), 4.37 (dd, J=10.2, 3.9 Hz, 1H), 2.36 (s, 3H);

ESIMS m/z: [M−H]⁻ 280, 282.

Step 6

N-{6-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-3-yl}acrylamide(Compound 166-6)

Compound 166-6 was obtained as a crude product in the same manner asstep 4 of example 162, using compound 166-5, and used as it is in thenext reaction.

ESIMS m/z: [M+H]⁺ 330.

Step 7

N-(5-Hydroxy-6-methyl-2,3-dihydrobenzofuran-3-yl)acrylamide (Compound166-7)

Compound 166-7 (8 mg, 16% over two steps) was obtained in the samemanner as step 5 of example 162, using compound 166-6.

¹H-NMR (400 MHz, CD₃OD, δ): 6.73 (s, 1H), 6.56 (s, 1H), 6.24-6.23 (m,2H), 5.66 (dd, J=8.6, 3.6 Hz, 1H), 5.52 (dd, J=7.9, 4.3 Hz, 1H), 4.60(dd, J=10.0, 8.2 Hz, 1H), 4.21 (dd, J=9.7, 4.3 Hz, 1H), 2.15 (s, 3H);

ESIMS m/z: [M+H]⁺ 220.

Step 8

N-{6-Methyl-5-[4-(trifluoromethyl)phenoxy]-2,3-dihydrobenzofuran-3-yl}acrylamide(Compound 266)

Compound 266 (5.5 mg, 62%) was obtained in the same manner as step 3 ofexample 1, using compound 166-7 (5.4 mg, 0.025 mmol),

¹H-NMR (400 MHz, CDCl₃, δ): 7.53 (d, J=10.0 Hz, 2H), 6.99 (s, 1H), 6.89(d, J=8.6 Hz, 2H), 6.79 (s, 1H), 6.33 (dd, J=16.8, 1.4 Hz, 1H), 6.05(dd, J=17.0, 10.2 Hz, 1H), 5.83 (br, 1H), 5.70 (dd, J=10.4, 1.4 Hz, 1H),5.67-5.65 (m, 1H), 4.78 (dd, J=10.2, 7.9 Hz, 1H), 4.40 (dd, J=10.2, 3.9Hz, 1H), 2.15 (s, 3H);

ESIMS m/z: [M−H]⁻ 362.

Example 167

Step 1

4-Methoxy-2-methylbenzo[d]oxazole-7-carbonitrile (Compound 167-1)

Compound 167-1 (0.30 g, 43%) was obtained in the same manner as step 6of example 144, using compound 143-3.

¹H NMR (400 MHz, CDCl₃, δ): 7.56 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.6 Hz),4.10 (s, 3H), 2.69 (s, 3H);

ESIMS m/z: [M+H]⁺ 189.

Step 2

4-Hydroxy-2-methylbenzo[d]oxazole-7-carbonitrile (Compound 167-2)

Compound 167-2 (0.85 g, 63%) was obtained in the same manner as step 4of example 144, using compound 167-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 11.54 (brs, 1H), 7.64 (d, J=8.4 Hz, 1H),6.84 (d, J=8.4 Hz, 1H), 2.64 (s, 3H);

ESIMS m/z: [M+H]⁺ 175.

Step 3

7-Cyano-2-methylbenzo[d]oxazol-4-yl trifluoromethanesulfonate (Compound167-3)

Compound 167-2 (0.3 g, 1.72 mmol) was dissolved in dichloromethane (5mL), and triethylamine (0.72 mL, 5.17 mmol) and trifluoromethanesulfonicanhydride (0.43 mL, 2.58 mmol) were added to the solution at 0° C. Themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure to obtain compound 167-3 as a crudeproduct, which was used as it is in the next reaction.

ESIMS m/z: [M−H]⁻ 305.

Step 4

(E)-2-Methyl-4-{4-(trifluoromethyl)styryl}benzo[d]oxazole-7-carbonitrile(Compound 167-4)

Compound 167-3 (0.9 g, 2.94 mmol) was dissolved in THF (10 mL), and1-(trifluoromethyl)-4-vinylbenzene (0.26 mL, 1.76 mmol), palladiumacetate (0.066 g, 0.29 mmol), 2,2-bis(diphenylphosphino)-1,1′-binaphthyl(0.366 g, 0.59 mmol) and N,N-diisopropylamine (2.56 mL, 14.7 mmol) wereadded to the solution. The solution was deaerated in Ar atmosphere for 5minutes, and then stirred at 70° C. in a sealed tube for 16 hours. Themixture was cooled to room temperature, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=95/5) to obtain compound 167-4 (0.17 g,18% over two steps).

¹H NMR (500 MHz, CDCl₃, δ): 7.94 (d, J=16.5 Hz, 1H), 7.73 (d, J=8.2 Hz,2H), 7.65 (d, J=8.0 Hz, 2H), 7.58-7.50 (m, 3H), 2.77 (s, 3H);

ESIMS m/z: [M+H]⁺ 329.

Step 5

2-Methyl-4-{4-(trifluoromethyl)phenethyl}benzo[d]oxazole-7-carbonitrile(Compound 167-5)

Compound 167-5 (0.14 g) was obtained as a crude product in the samemanner as step 1 of example 116, using compound 167-4, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 331.

Step 6

[2-Methyl-4-{4-(trifluoromethyl)phenethyl}benzo[d]oxazol-7-yl]methanamine(Compound 167-6)

Compound 167-6 (0.16 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 167-5, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 335.

Step 7

N-([2-Methyl-4-{4-(trifluoromethyl)phenethyl}benzo[d]oxazol-7-yl]methyl)acrylamide(Compound 267)

Compound 267 (0.012 g, 7% over three steps) was obtained in the samemanner as step 5 of example 1, using compound 167-6.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.63 (t, J=5.2 Hz, 1H), 7.62 (d, J=8.5 Hz,2H), 7.45 (d, J=8.0 Hz, 2H), 7.14-7.10 (m, 2H), 6.28 (dd, J=17.0, 10.0Hz, 1H), 6.14 (dd, J=17.0, 2.0 Hz, 1H), 5.62 (dd, J=10.0, 2.0 Hz, 1H),4.55 (d, J=6.0 Hz, 2H), 3.20-3.17 (m, 2H), 3.11-3.08 (m, 2H), 2.63 (s,3H);

ESIMS m/z: [M+H]⁺ 389.

Example 168

Step 1

Methyl 4-bromo-3-hydroxy-2-nitrobenzoate (Compound 168-1)

Commercially available methyl 3-hydroxy-2-nitrobenzoate (5.0 g, 25.38mmol) was dissolved in chloroform (60 mL), and bromine (2.6 mL, 50.76mmol) was added to the solution at room temperature. The mixture wasstirred at 60° C. for 20 hours. The mixture was cooled to roomtemperature and sodium pyrosulfite was added to the mixture. The organiclayer was extracted with dichloromethane. The organic layer obtained waswashed with saturated saline, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (petroleum ether/ethyl acetate=90/10) toobtain compound 168-1 (1.25 g, 18%).

¹H NMR (400 MHz, CDCl₃, δ): 10.66 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.15(d, J=9.0 Hz, 1H), 4.02 (s, 3H);

ESIMS m/z: [M−H]⁻ 274.

Step 2

Methyl 2-amino-4-bromo-3-hydroxybenzoate (Compound 168-2)

Compound 168-1 (3.5 g, 12.72 mmol) was dissolved in THF (80 mL), and anaqueous solution (80 mL) of sodium hydrosulfite (11.07 g, 63.64 mmol)was added to the solution at room temperature. The mixture was stirredat 60° C. for 1 hour. Water was added to the mixture, and the organiclayer was extracted with ethyl acetate. After pH of the water layer wasadjusted to 3, the organic layer was further extracted with ethylacetate, washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wascrystallized with n-pentane, and compound 168-2 (3.0 g, 96%) wasobtained by filtering the crystals obtained.

¹H NMR (500 MHz, CDCl₃, δ): 6.82 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.2 Hz,1H), 3.94 (s, 3H);

ESIMS m/z: [M+H]⁺ 246.

Step 3

Methyl 7-bromo-2-methylbenzo[d]oxazole-4-carboxylate (Compound 168-3)

Compound 168-3 (2.0 g, 62%) was obtained in the same manner as step 1 ofexample 147, using compound 168-2.

¹H NMR (500 MHz, CDCl₃, δ): 7.52 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz,1H), 4.06 (s, 3H), 2.67 (s, 3H);

ESIMS m/z: [M+H]⁺ 270.

Step 4

(7-Bromo-2-methylbenzo[d]oxazol-4-yl)methanol (Compound 168-4)

Compound 168-3 (2.0 g, 7.43 mmol) was dissolved in THF (20 mL), anddiisobutylaluminum hydride (22 mL, 22.3 mmol, 1.0 mol/L in THF) wasadded to the solution at 0° C. The mixture was stirred at roomtemperature for 1 hour. A saturated ammonium chloride aqueous solutionwas added to the mixture, and the organic layer was extracted with ethylacetate. The organic layer obtained was washed with a potassium sodiumtertrate aqueous solution and saturated saline, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=85/15) to obtain compound 168-4 (1.5 g, 84%).

¹H NMR (500 MHz, CDCl₃, δ): 7.47 (d, J=8.5 Hz, 1H), 7.28 (d, J=8.5 Hz,1H), 5.12 (d, J=4.3 Hz, 2H), 4.06 (brs, 1H), 2.65 (s, 3H);

ESIMS m/z: [M+H]⁺ 242.

Step 5

7-Bromo-2-methylbenzo[d]oxazole-4-carbaldehyde (Compound 168-5)

Compound 168-4 (1.5 g, 6.22 mmol) was dissolved in dichloromethane (70mL), and manganese oxide (15.70 g, 180.50 nmol) was added to thesolution at 0° C. The mixture was stirred at room temperature for 1hour. The mixture was filtered, and the filtrate obtained wasconcentrated under reduced pressure. The residue was crystallized withn-pentane, and compound 168-5 (1.1 g, 74%) was obtained by filtering thecrystals obtained.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.51 (s, 1H), 7.94 (d, J=8.6 Hz, 1H),7.72 (d, J=8.6 Hz, 1H), 2.70 (s, 3H);

ESIMS m/z: [M+H]⁺ 240.

Step 6

(7-Bromo-2-methylbenzo[d]oxazol-4-yl){4-(trifluoromethyl)phenyl}methanol(Compound 168-6)

1-Bromo-4-(trifluoromethyl)benzene (1.69 g, 7.53 mmol) was dissolved inTHF (5 mL), and isopropylmagnesium chloride lithium chloride complex(5.21 mL, 6.78 mmol, 1.3 mol/L in THF) was added to the solution. Themixture was stirred at 40° C. for 1 hour. Then, the mixture was cooledto 0° C., and a solution of compound 168-5 (0.9 g, 3.76 mmol) in THF (5mL) was added to the mixture. The resultant mixture was stirred at roomtemperature for 30 minutes. A saturated ammonium chloride aqueoussolution was added to the mixture and the organic layer was extractedwith ethyl acetate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=90/10) to obtaincompound 168-6 (0.55 g, 38%).

ESIMS m/z: [M+H]⁺ 386.

Step 7

4-[Hydroxy{4-(trifluoromethyl)phenyl}methyl]-2-methylbenzo[d]oxazole-7-carbonitrile(Compound 168-7)

Compound 168-7 (0.28 g, 59%) was obtained in the same manner as step 6of example 144, using compound 168-6.

ESIMS m/z: [M−H]⁻ 331.

Step 8

{7-(Aminomethyl)-2-methylbenzo[d]oxazol-4-yl}{4-(trifluoromethyl)phenyl}methanol(Compound 168-8)

Compound 168-8 (0.27 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 168-7, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 337.

Step 9

N-{(4-[Hydroxy{4-(trifluoromethyl)phenyl}methyl]-2-methylbenzo[d]oxazol-7-yl)methyl}acrylamide(Compound 268)

Compound 268 (0.028 g, 9% over two steps) was obtained in the samemanner as step 1 of example 76, using compound 167-8.

¹H NMR (400 MHz, DMSO-d₅, δ): 8.61 (t, J=5.5 Hz, 1H), 7.64 (s, 4H), 7.38(d, J=7.9 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.32 (d, J=4.4 Hz, 1H), 6.26(dd, J=17.2, 10.0 Hz, 1H), 6.18 (d, J=4.4 Hz, 1H), 6.11 (dd, J=16.8, 2.0Hz, 1H), 5.61 (dd, J=10.2, 2.3 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 2.64 (s,3H);

ESIMS m/z: [M+H]⁺ 391.

Example 169

Step 1

2-Methyl-4-[{4-(trifluoromethyl)phenyl}amino]benzo[d]oxazole-7-carbonitrile(Compound 169-1)

Compound 167-3 (0.32 g, 1.04 mmol) was dissolved in toluene (5 mL), and4-(trifluoromethyl)aniline (0.09 mL, 0.73 mmol),bis(dibenzylideneacetone)palladium(0) (0.12 g, 0.21 mmol),1,1-bis(diphenylphosphino)ferrocene (0.057 g, 0.104 mmol) and sodiumtert-butoxide (0.150 g, 1.57 mmol) were added to the solution. Themixture was deaerated in Ar atmosphere for 5 minutes, and then stirredat 80° C. for 6 hours. The mixture was cooled to room temperature, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (petroleum ether/ethyl acetate=80/20) to isobtain compound 169-1 (0.080 g, 24%).

¹H NMR (400 MHz, CDCl₃, δ): 7.63 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz,1H), 7.35 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.8 Hz, 1H), 7.13 (br s, 1H),2.71 (s, 3H);

ESIMS m/z: [M+H]⁺ 318.

Step 2

2-Methyl-4-[methyl{4-(trifluoromethyl)phenyl}amino]benzo[d]oxazole-7-carbonitrile(Compound 169-2)

Compound 169-1 (0.150 g, 0.47 mmol) was dissolved in THF (3 mL), andsodium hydride (60%, 0.037 g, 0.95 mmol) was added to the solution at 0°C. The mixture was stirred for 15 minutes. Then, Methyl iodide (0.058mL, 0.95 mmol) was added to the mixture, and the resultant mixture wasstirred at room temperature for 3 hours. Iced water was added to themixture and the organic layer was extracted with ethyl acetate, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (petroleumether/ethyl acetate=95/5) to obtain compound 169-2 (0.080 g, 51%).

¹H NMR (500 MHz, CDCl₃, δ): 7.56 (d, J=8.5 Hz, 2H), 7.40 (d, J=9.0 Hz,1H), 7.18 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), 2.66(s, 3H);

ESIMS m/z: [M+H]⁺ 332.

Step 3

7-(Aminomethyl)-N,2-dimethyl-N-{4-(trifluoromethyl)phenyl}benzo[d]oxalozol-4-amine(Compound 169-3)

Compound 169-3 (0.080 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 169-2, and used as it isin the next reaction.

ESIMS m/z: [M−NH₂]⁻ 319.

Step 4

N-{(2-Methyl-4-[methyl{4-(trifluoromethyl)phenyl}amino]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 269)

Compound 269 (0.016 g, 17% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 169-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.70 (t, J=5.5 Hz, 1H), 7.46 (d, J=8.8 Hz,2H), 7.28-7.20 (m, 2H), 6.81 (d, J=8.8 Hz, 2H), 6.31 (dd, J=16.8, 10.0Hz, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.64 (dd, J=10.1, 2.2 Hz, 1H),4.61 (d, J=5.7 Hz, 2H), 3.41 (s, 3H), 2.60 (s, 3H);

ESIMS m/z: [M+H]⁺ 390.

Example 170 Step 17-(Aminomethyl)-2-methyl-N-{4-(trifluoromethyl)phenyl}benzo[d]oxazol-4-amine(Compound 170-1)

Compound 170-1 (0.110 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 169-1, and used as it isin the next reaction.

ESIMS m/z: [M−NH₂]⁻ 305.

Step 2

N-{(2-Methyl-4-[{4-(trifluoromethyl)phenyl}amino]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 270)

Compound 270 (0.020 g, 14% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 170-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.88 (s, 1H), 8.61 (t, J=5.2 Hz, 1H), 7.50(d, J=8.4 Hz, 2H), 7.19-7.17 (m, 4H), 6.29 (dd, J=17.2, 10.0 Hz, 1H),6.14 (dd, J=17.2, 2.0 Hz, 1H), 5.63 (dd, J=10.0, 2.0 Hz, 1H), 4.55 (d,J=6.0 Hz, 2H), 2.62 (s, 3H);

ESIMS m/z: [M+H]⁺ 376.

Example 171

Step 1

2-Methyl-4-[{4-(trifluoromethyl)phenyl}thio]benzo[d]oxazole-7-carbonitrile(Compound 171-1)

Compound 167-3 (0.5 g, 1.63 mmol) was dissolved in DMF (5 mL), and4-(trifluoromethyl)benzenethiol (0.156 mL, 1.14 mmol), palladium acetate(0.110 g, 0.16 mmol), 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene(0.094 g, 0.16 mmol) and N,N-diisopropylamine (1.42 mL, 8.17 mmol) wereadded to the solution. The solution was deaerated in Ar atmosphere for 5minutes, and then stirred at 100° C. in a sealed tube for 4 hours. Themixture was cooled to room temperature, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=95/5) to obtain compound 171-1 (0.12 g,21% over two steps).

¹H NMR (500 MHz, CDCl₃, δ): 7.67 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz,2H), 7.43 (d, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 2.74 (s, 3H);

ESIMS m/z: [M+H]⁺ 335.

Step 2

(2-Methyl-4-[{4-(trifluoromethyl)phenyl}thio]benzo[d]oxazol-7-yl)methanamine(Compound 171-2)

Compound 171-2 (0.120 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 171-1, and used as it isin the next reaction.

ESIMS m/z: [M−NH₇]⁻ 322.

Step 3

N-{(2-Methyl-4-[{4-(trifluoromethyl)phenyl}thio]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 272)

Compound 272 (0.025 g, 18% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 171-2.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.75 (t, J=5.7 Hz, 1H), 7.63 (d, J=8.3 Hz,2H), 7.44 (d, J=7.9 Hz, 1H), 7.30-7.28 (m, 3H), 6.30 (dd, J=17.2, 10.0Hz, 1H), 6.15 (dd, J=17.2, 2.4 Hz, 1H), 5.65 (dd, J=10.3, 2.0 Hz, 1H),4.64 (d, J=6.1 Hz, 2H), 2.63 (s, 3H);

ESIMS m/z: [M+H]⁺ 393.

Step 4

N-{(2-Methyl-4-[{4-(trifluoromethyl)phenyl}sulfonyl]benzo[d]oxazol-7-yl)methyl}acrylamide(Compound 271)

Compound 272 (0.150 g, 0.38 mmol) was dissolved in dichloromethane (4mL), and m-chloroperoxybenzoic acid (0.198 g, 1.15 mmol) was added tothe solution at 0° C. The mixture was stirred at room temperature for 2hours. Dichloromethane was added to the mixture, and the organic layerwas washed with a saturated sodium bicarbonate aqueous solution andsaturated saline, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified using a preparativeHPLC to obtain compound 271 (0.023 g, 14%).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=5.7 Hz, 1H), 8.30 (d, J=8.3 Hz,2H), 8.00 (d, J=7.9 Hz, 3H), 7.45 (d, J=8.1 Hz, 1H), 6.28 (dd, J=17.2,10.0 Hz, 1H), 6.12 (dd, J=17.2, 2.4 Hz, 1H), 5.65 (dd, J=10.1, 2.2 Hz,1H), 4.63 (d, J=5.9 Hz, 2H), 2.69 (s, 3H),

ESIMS m/z: [M+H]⁺ 425.

Example 172

Step 1

(E)-[2-Methyl-4-{4-(trifluoroethyl)styryl}benzo[d]oxazol-7-yl]methanamine(Compound 172-1)

Compound 172-1 (0.13 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 167-4, and used as it isin the next reaction.

ESIMS m/z: [M−NH₂]⁻ 316.

Step 2

(E)-N-([2-Methyl-4-{4-(trifluoromethyl)styryl}benzo[d]oxazol-7-yl]methyl)acrylamide(Compound 273)

Compound 273 (0.021 g, 15% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 172-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.70-8.68 (m, 1H), 7.92 (d, J=16.4 Hz,1H), 7.85 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.63 (d, J=16.4 Hz,1H), 7.56 (d, J=7.9 Hz, 1H), 7.25 (d, J=7.9 Hz, 1H), 6.31 (dd, J=17.2,10.0 Hz, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.64 (dd, J=10.2, 2.1 Hz,1H), 4.62 (d, J=5.5 Hz, 2H), 2.70 (s, 3H),

ESIMS m/z: [M+H]⁺ 387.

Example 173

Step 1

2-Methyl-4-nitrobenzo[d]oxazole (Compound 173-1)

Compound 173-1 (11.0 g, 95%) was obtained in the same manner as step 1of example 147, using commercially available 2-amino-3-nitrophenol.

¹H NMR (400 MHz, CDCl₃, δ): 8.18 (dd, J=8.3, 0.8 Hz, 1H), 7.83 (dd,J=8.2, 0.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 2.79 (s, 3H);

ESIMS m/z: [M+H]⁺ 179.

Step 2

2-Methylbenzo[d]oxazol-4-amine (Compound 173-2)

Compound 173-1 (11.0 g, 61.79 mmol) was dissolved in THF (50 mL),ethanol (50 mL), and water (50 mL), and iron powder (17.30 g, 308.99mmol) and ammonium chloride (4.91 g, 92.70 mmol) were added to thesolution at room temperature. The mixture was stirred at 70° C. for 2hours. The mixture was cooled to room temperature, and concentratedunder reduced pressure. The residue/organic layer was extracted withethyl acetate, washed with saturated saline, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wascrystallized with n-pentane, and compound 173-2 (9.2 g, quantitatively)was obtained by filtering the crystals obtained.

¹H NMR (400 MHz, CDCl₃, δ): 7.51 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz,1H), 5.99 (s, 1H), 4.31 (brs, 2H), 3.86 (s, 3H);

ESIMS m/z: [M+H]⁺ 149.

Step 3

7-Bromo-2-methylbenzo[d]oxazol-4-amine (Compound 173-3)

Compound 173-3 (0.55 g, 51%) was obtained in the same manner as step 1of example 117, using compound 173-2.

¹H NMR (500 MHz, CDCl₃, δ): 7.18 (d, J=8.5 Hz, 1H), 6.48 (d, J=8.5 Hz,1H), 2.64 (s, 3H);

ESIMS m/z: [M+H]⁺ 227.

Step 4

N-(7-Bromo-2-methylbenzo[d]oxazol-4-yl)-4-(trifluoromethyl)benzamide(Compound 173-4)

Commercially available 4-(trifluoromethyl)benzoic acid (0.34 g, 1.77mmol) was dissolved in DMF (15 mL), and(1-cyano-2-ethoxy-2-oxoethylidenaminoxy)dimethylamino-morpholino-carbenium hexafluorophosphate (1.13 g, 2.65 mmol) and N,N-diisopropylamine(0.92 mL, 5.31 mmol) were added to the solution. The mixture was stirredat room temperature for 15 minutes. Then, compound 173-3 (0.4 g, 1.77mmol) was added to the mixture. The mixture was further stirred at roomtemperature for 16 hours. Water was added to the mixture and the organiclayer was extracted with ethyl acetate, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate=95/5) to obtain compound 173-4 (0.13 g, 18%).

¹H NMR (500 MHz, CDCl₃, δ): 8.71 (brs, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.08(d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.48 (d, J=9.0 Hz, 1H), 2.70(s, 3H);

ESIMS m/z: [M+H]⁺ 399.

Step 5

N-(7-Cyano-2-methylbenzo[d]oxazol-4-yl)-4-(trifluoromethyl)benzamide(Compound 173-5)

Compound 173-5 (0.17 g, 56%) was obtained in the same manner as step 6of example 144, using compound 173-4.

¹H NMR (400 MHz, CDCl₃, δ): 8.91 (brs, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.10(d, J=7.9 Hz, 2H), 7.82 (d, J=7.9 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 2.74(s, 3H);

ESIMS m/z: [M+H]⁺ 346.

Step 6

N-{7-(Aminomethyl)-2-methylbenzo[d]oxazol-4-yl}-4-(trifluoromethyl)benzamide(Compound 173-6)

Compound 173-6 (0.18 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 173-5, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 350.

Step 7

N-{7-(Acrylamidemethyl)-2-methylbenzo[d]oxazol-4-yl}-4-(trifluoromethyl)benzamide(Compound 274)

Compound 274 (0.050 g, 25% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 173-6.

¹H NMR (500 MHz, DMSO-d₆, δ): 10.58 (s, 1H), 8.70 (t, J=5.8 Hz, 1H),8.21 (d, J=7.9 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.66 (d, J=7.9 Hz, 1H),7.24 (d, J=8.2 Hz, 1H), 6.30 (dd, J=17.5, 10.5 Hz, 1H), 6.15 (dd,J=17.2, 2.3 Hz, 1H), 5.64 (dd, J=10.0, 2.0 Hz, 1H), 4.60 (d, J=5.8 Hz,2H), 2.65 (s, 3H);

ESIMS m/z: [M+H]⁺ 404.

Example 174

Step 1

4-Hydroxy-2-methylbenzo[d]oxazole-7-carbonitrile (Compound 174-1)

Compound 174-1 (0.19 g, 25%) was obtained in the same manner as step 6of example 144, using compound 143-4.

¹H NMR (400 MHz, DMSO-d₆, δ): 11.57 (brs, 1H), 7.64 (d, J=8.6 Hz, 1H),6.84 (d, J=8.6 Hz, 1H), 2.64 (s, 3H);

ESIMS m/z: [M+H]⁺ 175.

Step 2

7-(Aminomethyl)-2-methylbenzo[d]oxazol-4-ol (Compound 174-2)

Compound 174-2 (0.18 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 174-1, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 179.

Step 3

N-{(4-Hydroxy-2-methylbenzo[d]oxazol-7-yl)methyl}acrylamide (Compound174-3)

Compound 174-2 (0.18 g, 1.01 mmol) was dissolved in THF (2 mL) and water(1 mL), and sodium hydrogen carbonate (0.17 g, 2.02 mmol) and acryloylchloride (0.065 mL, 0.81 mmol) were added to the solution at 0° C. Themixture was stirred at room temperature for 1 hour. Then, lithiumhydroxide monohydrate (0.085 g, 2.02 mmol) was added to the mixture. Themixture was further stirred for 1 hour. Water was added to the mixture.The organic layer was extracted with ethyl acetate, washed withsaturated saline, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (petroleum ether/ethyl acetate=30/70) toobtain compound 174-3 (0.13 g) as a crude product.

ESIMS m/z: [M+H]⁺ 233.

Step 4

N-([4-{4-(Dimethylamino)phenoxy}-2-methylbenzo[d]oxazol-7-yl]methyl)acrylamide(Compound 275)

Compound 174-3 (0.17 g, 0.73 mmol) was dissolved in dichloromethane (5mL), and {4-(dimethylamino)phenyl}boronic acid (0.423 g, 2.56 mmol),pyridine (0.29 mL, 3.66 mmol), copper(II) acetate (0.265 g, 1.46 mmol)and molecular sieve 4 angstrom (200 mg) were added to the solution. Themixture was stirred in oxygen atmosphere at room temperature overnight.The mixture was concentrated under reduced pressure. The residue waspurified using a preparative HPLC to obtain compound 275 (0.034 g, 13%over three steps).

¹H NMR (400 MHz, DMSO-d₆, δ): 8.60 (brs, 1H), 7.13 (d, J=8.3 Hz, 1H),6.92 (d, J=9.0 Hz, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.64 (d, J=8.3 Hz, 1H),6.27 (dd, J=17.0, 10.0 Hz, 1H), 6.11 (dd, J=17.2, 2.0 Hz, 1H), 5.61 (dd,J=10.0, 2.0 Hz, 1H), 4.53 (d, J=5.6 Hz, 2H), 2.87 (s, 6H), 2.61 (s, 3H);

ESIMS m/z: [M+H]⁺ 352.

Example 175

Step 1

7-Bromo-4-(cyclohexyloxy)-2-methylbenzo[d]oxazole (Compound 175-1)

Compound 143-4 (1.0 g, 4.38 mmol) was dissolved in acetonitrile (20 mL),and bromocyclohexane (2.84 g, 17.54 mmol) and potassium carbonate (1.21g, 8.77 mmol) were added to the solution. The mixture was stirred at 70°C. for 72 hours. The mixture was filtered with Celite®, and washed withacetonitrile. The organic layer was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (petroleumether/ethyl acetate=85/15→80/20) to obtain compound 175-1 (0.30 g, 22%).

¹H NMR (500 MHz, CDCl₃, δ): 7.29 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.5 Hz,1H), 4.59-4.55 (m, 1H), 2.66 (s, 3H), 2.08-2.05 (m, 2H), 1.85-1.78 (m,3H), 1.31-1.42 (m, 5H);

ESIMS m/z: [M+H]⁺ 310.

Step 2

4-(Cyclohexyloxy)-2-methylbenzo[d]oxazole-7-carbonitrile (Compound175-2)

Compound 175-2 (0.15 g, 73%) was obtained in the same manner as step 6of example 144, using compound 175-1.

ESIMS m/z: [M+H]⁺ 257.

Step 3

{4-(Cyclohexyloxy)-2-methylbenzo[d]oxazol-7-yl}methanamine (Compound175-3)

Compound 175-3 (0.16 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 175-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 261.

Step 4

N-[{4-(Cyclohexyloxy)-2-methylbenzo[d]oxazol-7-yl}methyl]acrylamide(Compound 276)

Compound 276 (0.030 g, 16% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 175-3.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.57 (t, J=5.0 Hz, 1H), 7.10 (d, J=8.5 Hz,1H), 6.86 (d, J=8.5 Hz, 1H), 6.26 (dd, J=17.0, 10.0 Hz, 1H), 6.13 (dd,J=17.0, 2.0 Hz, 1H), 5.61 (dd, J=10.0, 2.0 Hz, 1H), 4.74-4.70 (m, 1H),4.50 (d, J=5.5 Hz, 2H), 2.59 (s, 3H), 1.92 (brs, 2H), 1.74-1.72 (m, 2H),1.54-1.44 (m, 3H), 1.40-1.36 (m, 3H);

ESIMS m/z: [M+H]⁺ 315.

Example 176

Step 1

7-Bromo-4-{3-fluoro-4-(trifluoromethyl)phenoxy}-2-methylbenzo[d]oxazole(Compound 176-1)

Compound 176-1 (0.55 g, 64%) was obtained in the same manner as step 1of example 3, using compound 143-4 and3-fluoro-4-(trifluoromethyl)phenylboronic acid.

¹H NMR (500 MHz, CDCl₃, δ): 7.54 (t, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz,1H), 6.93 (d, J=8.5 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.79 (d, J=12.0 Hz,1H), 2.67 (s, 3H);

ESIMS m/z: [M+H]⁺ 390.

Step 2

4-{3-Fluoro-4-(trifluoromethyl)phenoxy}-2-methylbenzo[d]oxazole-7-carbonitrile(Compound 176-2)

Compound 176-2 (0.23 g, 48%) was obtained in the same manner as step 6of example 144, using compound 176-1.

¹H NMR (500 MHz, CDCl₃, δ): 7.64-7.59 (m, 2H), 6.99-6.90 (m, 3H), 2.72(s, 3H);

ESIMS m/z: [M+H]⁺ 337.

Step 3

[4-{3-Fluoro-4-(trifluoromethyl)phenoxy}-2-methylbenzo[d]oxazol-7-yl]methanamine(Compound 176-3)

Compound 176-3 (0.20 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 176-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 341.

Step 4

N-([4-{3-Fluoro-4-(trifluoromethyl)phenoxy}-2-methylbenzo[d]oxazol-7-yl]methyl)acrylamide(Compound 277)

Compound 277 (0.078 g, 29% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 176-3.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.73 (t, J=4.5 Hz, 1H), 7.73 (t, J=8.7 Hz,1H), 7.31 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.14 (d, J=12.5 Hz,1H), 6.86 (d, J=9.0 Hz, 1H), 6.31 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (d,J=17.0 Hz, 1H), 5.65 (d, J=10.0 Hz, 1H), 4.62 (d, J=5.5 Hz, 2H), 2.64(s, 3H);

ESIMS m/z: [M+H]⁺ 395.

Example 177N-[{4-(4-Cyanophenoxy]-2-methylbenzo[d]oxazol-7-yl}methyl)acrylamide(Compound 278)

Compound 278 (0.032 g, 17%) was obtained in the same manner as step 4 ofexample 174, using compound 174-3 and 4-cyano phenylboronic acid.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.72 (brs, 1H), 7.81 (d, J=8.5 Hz, 2H),7.30 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H),6.30 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (dd, J=17.0, 1.8 Hz, 1H), 5.65 (dd,J=10.3, 1.8 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.59 (s, 3H);

ESIMS m/z: [M+H]⁺ 334.

Example 178

Step 1

7-Bromo-2-methyl-4-{3-(trifluoromethyl)phenoxy}benzo[d]oxazole (Compound178-1)

Compound 178-1 (0.55 g) was obtained as a crude product in the samemanner as step 4 of example 174, using compound 143-4 and3-(trifluoromethyl)phenylboronic acid, and used as it is in the nextreaction.

ESIMS m/z: [M+H]⁺ 372.

Step 22-Methyl-4-{3-(trifluoromethyl)phenoxy}benzo[d]oxazole-7-carbonitrile(Compound 178-2)

Compound 178-2 (0.28 g, 40% over two steps) was obtained in the samemanner as step 6 of example 144, using compound 178-1.

¹H NMR (400 MHz, CDCl₃, δ): 7.57-7.50 (m, 3H), 7.39 (s, 1H), 7.32 (d,J=8.0 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 2.73 (s, 3H);

ESIMS m/z: [M+H]⁺ 319.

Step 3

[2-Methyl-4-{3-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methanamine(Compound 178-3)

Compound 178-3 (0.25 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 178-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 323.

Step 4

N-([2-Methyl-4-{3-(trifluoromethyl)phenoxy}benzo[d]oxazol-7-yl]methyl)acrylamide (Compound 279)

Compound 279 (0.046 g, 14% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 178-3.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.71 (t, J=5.5 Hz, 1H), 7.58 (t, J=8.0 Hz,1H), 7.47 (d, J=7.5 Hz, 1H), 7.30-7.21 (m, 3H), 7.08 (d, J=8.0 Hz, 1H),6.33-6.27 (dd, J=10.0, 17.0 Hz, 1H), 6.15 (dd, J=17.0, 2.0 Hz, 1H), 5.64(dd, J=10.2, 2.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.60 (s, 3H);

ESIMS m/z: [M+H]⁺ 377.

Example 179

Step 1

7-Bromo-4-(4-methoxyphenoxy)-2-methylbenzo[d]oxazole (Compound 179-1)

Compound 179-1 (0.55 g, 75%) was obtained in the same manner as step 4of example 174, using compound 143-4 and 4-methoxyphenyl boronic acid.

¹H NMR (500 MHz, DMSO-d₆, δ): 7.48 (d, J=8.5 Hz, 1H), 7.06-7.03 (m, 2H),6.99-6.96 (m, 2H), 6.68 (d, J=9.0 Hz, 1H), 3.76 (s, 3H), 2.64 (s, 3H);

ESIMS m/z: [M+H]⁺ 334.

Step 2

4-(4-Methoxyphenoxy)-2-methylbenzo[d]oxazole-7-carbonitrile (Compound179-2)

Compound 179-2 (0.28 g, 60%) was obtained in the same manner as step 6of example 144, using compound 179-1.

¹H NMR (500 MHz, CDCl₃, δ): 7.44 (d, J=8.5 Hz, 1H), 7.10-7.08 (m, 2H),6.96-6.94 (m, 2H), 6.62 (d, J=8.5 Hz, 1H), 3.84 (s, 3H), 2.73 (s, 3H);

ESIMS m/z: [M+H]⁺ 281.

Step 3

N-[{4-(4-Methoxyphenoxy]-2-methylbenzo[d]oxazol-7-yl}methyl)acrylamide(Compound 280)

Compound 280 (0.030 g, 19%) was obtained in the same manner as step 7 ofexample 148, using compound 179-2.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.64 (t, J=5.3 Hz, 1H), 7.16 (d, J=8.5 Hz,1H), 6.99-6.92 (m, 4H), 6.74 (d, J=8.5 Hz, 1H), 6.28 (dd, J=17.0, 10.5Hz, 1H), 6.13 (dd, J=17.5, 2.5 Hz, 1H), 5.62 (dd, J=10.2, 2.0 Hz, 1H),4.55 (d, J=5.5 Hz, 2H), 3.74 (s, 3H), 2.61 (s, 3H);

ESIMS m/z: [M+H]⁺ 339.

Example 180N-[{4-(4-Chlorophenoxy]-2-methylbenzo[d]oxazol-7-yl}methyl)acrylamide(Compound 281)

Compound 281 (0.022 g, 15%) was obtained in the same manner as step 4 ofexample 174, using compound 174-3 and 4-chiorophenyl boronic add.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.69 (t, J=5.3 Hz, 1H), 7.40 (d, J=8.5 Hz,2H), 7.24 (d, J=8.5 Hz, 1H), 6.99-6.97 (m, 3H), 6.29 (dd, J=17.0, 10.0Hz, 1H), 6.14 (dd, J=17.0, 2.0 Hz, 1H), 5.64 (dd, J=10.0, 2.0 Hz, 1H),4.59 (d, J=6.0 Hz, 2H), 2.60 (s, 3H);

ESIMS m/z: [M+H]⁺ 343.

Example 181

Step 1

4-(Benzyloxy)-7-bromo-2-methylbenzo[d]oxazole (Compound 181-1)

Compound 181-1 (0.50 g, 89%) was obtained in the same manner as step 1of example 175, using compound 143-4 and benzyl bromide.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.49-7.47 (m, 3H), 7.45-7.39 (m, 2H),7.37-7.35 (m, 1H), 6.98 (d, J=8.8 Hz, 1H), 5.34 (s, 2H), 2.63 (a, 3H);

ESIMS m/z: [M+H]⁺ 318.

Step 2

4-(Benzyloxy)-2-methylbenzo[d]oxazole-7-carbonitrile (Compound 181-2)

Compound 181-2 (0.20 g, 53%) was obtained in the same manner as step 6of example 144, using compound 181-1.

¹H NMR (400 MHz, DMSO-d₆, δ): 7.82 (d, J=8.8 Hz, 1H), 7.51-7.49 (m, 2H),7.45-7.37 (m, 3H), 7.18 (d, J=8.8 Hz, 1H), 5.45 (s, 2H), 2.66 (s, 3H);

ESIMS m/z: [M+H]⁺ 265.

Step 3

N-[{4-(Benzyloxy)-2-methylbenzo[d]oxazol-7-yl}methyl]acrylamide(Compound 282)

Compound 282 (0.035 g, 14%) was obtained in the same manner as step 7 ofexample 148, using compound 181-2.

¹H NMR (500 MHz, DMSO-d₅, δ): 8.58 (t, J=5.5 Hz, 1H), 7.48-7.47 (m, 2H),7.41-7.38 (m, 2H), 7.35-7.32 (m, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.94 (d,J=8.5 Hz, 1H), 6.27 (dd, J=17.0, 10.5 Hz, 1H), 6.12 (dd, J=17.5, 2.5 Hz,1H), 5.61 (dd, J=10.0, 2.0 Hz, 1H), 5.33 (s, 2H), 4.50 (d, J=5.5 Hz,2H), 2.60 (s, 3H);

ESIMS m/z: [M+H]⁺ 323.

Example 182

Step 1

4-Bromo-2-methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazole(Compound 182-1)

Compound 153-4 (1.0 g, 4.38 mmol) was dissolved in DMF (10 mL), and5-bromo-2-(trifluoromethyl)pyridine (1.98 g, 8.77 mmol) and cesiumcarbonate (2.86 g, 8.77 mmol) were added to the solution. The mixturewas stirred at 145° C. for 1 hour using a micro-wave reaction apparatusBiotage® Initiator. The mixture was cooled to room temperature, andwater was added to the mixture. The organic layer was extracted withethyl acetate, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=95/5) to obtain compound182-1 (0.40 g, 24%).

¹H NMR (500 MHz, CDCl₃, δ): 8.52 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.8 Hz,1H), 7.51 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.0, 2.8 Hz, 1H), 6.98 (d,J=8.4 Hz, 1H), 2.71 (s, 3H);

ESIMS m/z: [M+H]⁺ 373.

Step 2

2-Methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazole-4-carbonitrile(Compound 182-2)

Compound 182-2 (0.18 g, 52%) was obtained in the same manner as step 6of example 144, using compound 182-1.

¹H NMR (500 MHz, CDCl₃, δ): 8.58 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.64(d, J=8.5 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 2.71(s, 3H);

ESIMS m/z: [M+H]⁺ 320.

Step 3

(2-Methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazol-4-yl)methanamine(Compound 182-3)

Compound 182-3 (0.14 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 182-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 324.

Step 4

N-{(2-Methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]oxazol-4-yl)methyl}acrylamide(Compound 283)

Compound 283 (0.031 g, 14% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 182-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.68 (t, J=5.6 Hz, 1H), 8.64 (d, J=2.4 Hz,1H), 7.89 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.6, 2.7 Hz, 1H), 7.29-7.21 (m,2H), 6.33 (dd, J=17.2, 10.4 Hz, 1H), 6.14 (dd, J=17.2, 2.0 Hz, 1H), 5.63(dd, J=10.4, 2.0 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 2.61 (s, 3H);

ESIMS m/z: [M+H]⁺ 378.

Example 183

Step 1

4-Bromo-2-methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazole(Compound 183-1)

Compound 183-1 (0.45 g, 55%) was obtained in the same manner as step 1of example 182, using compound 153-4 and2-chloro-5-(trifluoromethyl)pyridine.

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (s, 1H), 7.99 (dd, J=8.8, 2.4 Hz, 1H),7.51 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H),2.63 (s, 3H);

ESIMS m/z: [M+H]⁺ 373.

Step 2

2-Methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazole-4-carbonitrile(Compound 183-2)

Compound 183-2 (0.12 g, 46%) was obtained in the same manner as step 6of example 144, using compound 183-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.37 (s, 1H), 8.03 (dd, J=8.8, 2.4 Hz, 1H),7.68 (d, J=8.4 Hz, 1H), 7.26-7.23 (m, 2H), 2.67 (s, 3H);

ESIMS m/z: [M+H]⁺ 320.

Step 3

(2-Methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazol-4-yl)methanamine(Compound 183-3)

Compound 183-3 (0.14 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 183-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 324.

Step 4

N-{(2-Methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]oxazol-4-yl)methyl}acrylamide(Compound 284)

Compound 284 (0.018 g, 13% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 183-3.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.70 (s, 1H), 8.54 (s, 1H), 8.30 (d, J=8.5Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.27-7.22 (m, 2H), 6.32 (dd, J=17.0,10.0 Hz, 1H), 6.14 (d, J=17.0 Hz, 1H), 5.63 (d, J=10.0 Hz, 1H), 4.65 (d,J=5.5 Hz, 2H), 2.58 (s, 3H);

ESIMS m/z: [M+H]⁺ 378.

Example 184

Step 1

7-Bromo-2-methyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazole(Compound 184-1)

Compound 184-1 (0.60 g, 54%) was obtained in the same manner as step 1of example 182, using compound 156-4.

¹H NMR (500 MHz, CDCl₃, δ): 8.52 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.5 Hz,1H), 7.49 (d, J=8.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.00 (d, J=8.5 Hz, 1H),2.82 (s, 3H);

ESIMS m/z: [M+H]⁺ 389.

Step 2

2-Methyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazole-7-carbonitrile(Compound 184-2)

Compound 184-2 (0.20 g, 39%) was obtained in the same manner as step 6of example 144, using compound 184-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.58 (d, J=2.8 Hz, 1H), 7.73 (d, J=8.4 Hz,1H), 7.69 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.03 (d,J=8.4 Hz, 1H), 2.90 (s, 3H);

ESIMS m/z: [M+H]⁺ 336.

Step 3

(2-Methyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazol-7-yl)methanamine(Compound 184-3)

Compound 184-3 (0.22 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 184-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 340.

Step 4

N-{(2-Methyl-4-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazol-7-yl)methyl}acrylamide(Compound 285)

Compound 285 (0.018 g, 13% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 184-3.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.76 (s, 1H), 8.56 (s, 1H), 7.84 (d, J=9.0Hz, 1H), 7.42-7.35 (m, 3H), 6.31 (dd, J=17.0, 10.0 Hz, 1H), 6.18 (d,J=17.0 Hz, 1H), 5.67 (d, J=10.0 Hz, 1H), 4.60 (d, J=5.5 Hz, 2H), 2.75(s, 3H);

ESIMS m/z: [M+H]⁺ 394.

Example 185

Step 1

7-Bromo-2-methyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]thiazole(Compound 185-1)

Compound 185-1 (0.35 g, 55%) was obtained in the same manner as step 1of example 183, using compound 156-4.

¹H NMR (500 MHz, CDCl₃, δ): 8.36 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.52(d, J=8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 2.78(s, 3H);

ESIMS m/z: [M+H]⁺ 389.

Step 2

2-Methyl-4-[{5-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazole-7-carbonitrile(Compound 185-2)

Compound 185-2 (0.18 g, 60%) was obtained in the same manner as step 6of example 144, using compound 185-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.35 (d, J=2.4 Hz, 1H), 8.01 (dd, J=8.4, 2.4Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 2H), 2.83 (s, 3H);

ESIMS m/z: [M+H]⁺ 336.

Step 3

(2-Methyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]diazol-7-yl)methanamine(Compound 185-3)

Compound 185-3 (0.17 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 185-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 340.

Step 4

N-{(2-Methyl-4-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]thiazol-7-yl)methyl}acrylamide(Compound 286)

Compound 286 (0.018 g, 13% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 185-3.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=5.6 Hz, 1H), 8.47 (s, 1H), 8.23(dd, J=8.8, 2.4 Hz, 1H), 7.39-7.31 (m, 3H), 6.31 (dd, J=17.0, 10.0 Hz,1H), 6.16 (dd, J=17.0, 2.0 Hz, 1H), 5.65 (dd, J=10.0, 2.4 Hz, 1H), 4.58(d, J=5.6 Hz, 2H), 2.71 (s, 3H);

ESIMS m/z: [M+H]⁺ 394.

Example 186

Step 1

4-Bromo-2-methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazole(Compound 186-1)

Compound 186-1 (0.45 g, 36%) was obtained in the same manner as step 1of example 182, using compound 157-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.53 (d, J=2.4 Hz, 1H), 7.68-7.65 (m, 2H),7.37 (dd, J=8.8, 2.8 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 2.89 (s, 3H);

ESIMS m/z: [M+H]⁺ 389.

Step 2

2-Methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazole-4-carbonitrile(Compound 186-2)

Compound 186-2 (0.19 g, 55%) was obtained in the same manner as step 6of example 144, using compound 186-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.60 (d, J=2.8 Hz, 1H), 7.79-7.75 (m, 2H),7.54 (dd, J=8.8, 2.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 2.95 (s, 3H);

ESIMS m/z: [M+H]⁺ 336.

Step 3

N-{(2-Methyl-7-[{6-(trifluoromethyl)pyridin-3-yl}oxy]benzo[d]thiazol-4-yl)methyl}acrylamide(Compound 287)

Compound 287 (0.050 g, 22%) was obtained in the same manner as step 7 ofexample 148, using compound 186-2.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.70 (t, J=5.8 Hz, 1H), 8.64 (d, J=3.0 Hz,1H), 7.90 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.5, 2.5 Hz, 1H), 7.42 (d,J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.34 (dd, J=17.0, 10.0 Hz, 1H),6.15 (dd, J=17.0, 2.0 Hz, 1H), 5.64 (dd, J=10.0, 2.0 Hz, 1H), 4.82 (d,J=5.8 Hz, 2H), 2.84 (s, 3H);

ESIMS m/z: [M+H]⁺ 394.

Example 187

Step 1

4-Bromo-2-methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]thiazole(Compound 187-1)

Compound 187-1 (0.33 g, 52%) was obtained in the same manner as step 1of example 183, using compound 157-3.

¹H NMR (400 MHz, CDCl₃, δ): 8.40 (s, 1H), 7.96 (dd, J=8.4, 2.4 Hz, 1H),7.69 (d, J=8.4 Hz, 1H), 7.15-7.09 (m, 2H), 2.87 (s, 3H);

ESIMS m/z: [M+H]⁺ 389.

Step 2

2-Methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]thiazole-4-carbonitrile(Compound 187-2)

Compound 187-2 (0.19 g, 73%) was obtained in the same manner as step 6of example 144, using compound 187-1.

¹H NMR (400 MHz, CDCl₃, δ): 8.42 (s, 1H), 8.03 (dd, J=8.4, 2.4 Hz, 1H),7.83 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H),2.91 (s, 3H);

ESIMS m/z: [M+H]⁺ 336.

Step 3

(2-Methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]thiazol-4-yl)methanamine(Compound 187-3)

Compound 187-3 (0.15 g) was obtained as a crude product in the samemanner as step 3 of example 15, using compound 187-2, and used as it isin the next reaction.

ESIMS m/z: [M+H]⁺ 340.

Step 4

N-{(2-Methyl-7-[{5-(trifluoromethyl)pyridin-2-yl}oxy]benzo[d]thiazol-4-yl)methyl}acrylamide(Compound 288)

Compound 288 (0.045 g, 20% over two steps) was obtained in the samemanner as step 5 of example 1, using compound 187-3.

¹H NMR (500 MHz, DMSO-d₆, δ): 8.72 (t, J=5.8 Hz, 1H), 8.54 (s, 1H), 8.30(dd, J=8.8, 2.3 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H),7.30 (d, J=8.0 Hz, 1H), 6.34 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (dd,J=17.0, 2.0 Hz, 1H), 5.63 (dd, J=10.0, 2.0 Hz, 1H), 4.82 (d, J=5.8 Hz,2H), 2.82 (s, 3H);

ESIMS m/z: [M+H]⁺ 394.

The invention claimed is:
 1. An α,β-unsaturated amide compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

wherein R¹ represents a hydrogen atom or an optionally substituted lower alkyl, R² represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group, X represents —O—, —S—, —SO₂—, —NR^(X1)— wherein R^(X1) represents a hydrogen atom or lower alkyl, —CHR^(X2)— wherein R^(X2) represents a hydrogen atom or hydroxy, —CH═CH—, —CO— or —NH—CO—, n1 and n2 are the same or different, and each represents 0 or 1, and A represents optionally substituted heterocyclic diyl, wherein the heterocyclic diyl in the optionally substituted heterocyclic diyl is heterocyclic diyl selected from the group consisting of benzoxazolediyl, benzothiazolediyl, 2,3-dihydrobenzothiophenediyl, 3,4-dihydropyranopyridinediyl, 2,3,4,5-tetrahydrobenzoxazepinediyl, 2,3,4,5-tetrahydrobenzoxepinediyl and 2,3-dihydrobenzofurandiyl, and the benzothiazolediyl is benzothiazolediyl represented by the following formula (A2-1) or (A2-2):

wherein -[X] represents bonding position of the group represented in formula (A-1):

wherein X, R² and n2 are each the same as the definition described above, and -[ACP] represents bonding position of the group represented in formula (A-2):

wherein R¹ and n1 are each the same as the definition described above, and the 2,3-dihydrobenzofurandiyl is 2,3-dihydrobenzofurandiyl selected from the group consisting of the following formulae (A8-1), (A8-2) and (A8-3):

wherein -[X] and -[ACP] are each the same as the definition described above.
 2. The α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R¹ is a hydrogen atom.
 3. The α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R² is optionally substituted aryl or optionally substituted aromatic heterocyclic group.
 4. A pharmaceutical composition, comprising: the α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof according to claim 1; and a carrier.
 5. A therapeutic agent comprising the α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
 6. A method for treating cancer, comprising: administering the α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.
 7. A medicine, comprising the α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof according to claim
 1. 8. The method according to claim 6, wherein the cancers at least one selected from the group consisting of mesothelioma, lung cancer, ovarian cancer, and liver cancer. 